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  • 1.
    Ahsan, Muhammad
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ek, Weronica E
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Rask-Andersen, Mathias
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Karlsson, Torgny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lind-Thomsen, Allan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Enroth, Stefan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Gyllensten, Ulf B.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Johansson, Åsa
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    The relative contribution of DNA methylation and genetic variants on protein biomarkers for human diseases.2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 9, article id e1007005Article in journal (Refereed)
    Abstract [en]

    Associations between epigenetic alterations and disease status have been identified for many diseases. However, there is no strong evidence that epigenetic alterations are directly causal for disease pathogenesis. In this study, we combined SNP and DNA methylation data with measurements of protein biomarkers for cancer, inflammation or cardiovascular disease, to investigate the relative contribution of genetic and epigenetic variation on biomarker levels. A total of 121 protein biomarkers were measured and analyzed in relation to DNA methylation at 470,000 genomic positions and to over 10 million SNPs. We performed epigenome-wide association study (EWAS) and genome-wide association study (GWAS) analyses, and integrated biomarker, DNA methylation and SNP data using between 698 and 1033 samples depending on data availability for the different analyses. We identified 124 and 45 loci (Bonferroni adjusted P < 0.05) with effect sizes up to 0.22 standard units' change per 1% change in DNA methylation levels and up to four standard units' change per copy of the effective allele in the EWAS and GWAS respectively. Most GWAS loci were cis-regulatory whereas most EWAS loci were located in trans. Eleven EWAS loci were associated with multiple biomarkers, including one in NLRC5 associated with CXCL11, CXCL9, IL-12, and IL-18 levels. All EWAS signals that overlapped with a GWAS locus were driven by underlying genetic variants and three EWAS signals were confounded by smoking. While some cis-regulatory SNPs for biomarkers appeared to have an effect also on DNA methylation levels, cis-regulatory SNPs for DNA methylation were not observed to affect biomarker levels. We present associations between protein biomarker and DNA methylation levels at numerous loci in the genome. The associations are likely to reflect the underlying pattern of genetic variants, specific environmental exposures, or represent secondary effects to the pathogenesis of disease.

  • 2.
    Arendt, Maja Louise
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Univ Cambridge, Dept Vet Med, Cambridge, England..
    Melin, Malin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Tonomura, Noriko
    Broad Inst MIT & Harvard, Cambridge, MA USA.;Tufts Univ, Cummings Sch Vet Med, Dept Clin Sci, North Grafton, MA USA..
    Koltookian, Michele
    Broad Inst MIT & Harvard, Cambridge, MA USA..
    Courtay-Cahen, Celine
    Anim Hlth Trust, Newmarket, Suffolk, England..
    Flindall, Netty
    Anim Hlth Trust, Newmarket, Suffolk, England..
    Bass, Joyce
    Anim Hlth Trust, Newmarket, Suffolk, England..
    Boerkamp, Kim
    Univ Utrecht, Dept Clin Sci Compan Anim, Utrecht, Netherlands..
    Megquir, Katherine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Broad Inst MIT & Harvard, Cambridge, MA USA.;Tufts Univ, Cummings Sch Vet Med, Dept Clin Sci, North Grafton, MA USA..
    Youell, Lisa
    Anim Hlth Trust, Newmarket, Suffolk, England..
    Murphy, Sue
    Anim Hlth Trust, Newmarket, Suffolk, England..
    McCarthy, Colleen
    Broad Inst MIT & Harvard, Cambridge, MA USA..
    London, Cheryl
    Ohio State Univ, Dept Vet Clin Sci, Columbus, OH 43210 USA..
    Rutteman, Gerard R.
    Univ Utrecht, Dept Clin Sci Compan Anim, Utrecht, Netherlands.;Vet Specialist Ctr De Wagenrenk, Wageningen, Netherlands..
    Starkey, Mike
    Anim Hlth Trust, Newmarket, Suffolk, England..
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Broad Inst MIT & Harvard, Cambridge, MA USA..
    Genome-Wide Association Study of Golden Retrievers Identifies Germ-Line Risk Factors Predisposing to Mast Cell Tumours2015In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, no 11, article id e1005647Article in journal (Refereed)
    Abstract [en]

    Canine mast cell tumours (CMCT) are one of the most common skin tumours in dogs with a major impact on canine health. Certain breeds have a higher risk of developing mast cell tumours, suggesting that underlying predisposing germ-line genetic factors play a role in the development of this disease. The genetic risk factors are largely unknown, although somatic mutations in the oncogene C-KIT have been detected in a proportion of CMCT, making CMCT a comparative model for mastocytosis in humans where C-KIT mutations are frequent. We have performed a genome wide association study in golden retrievers from two continents and identified separate regions in the genome associated with risk of CMCT in the two populations. Sequence capture of associated regions and subsequent fine mapping in a larger cohort of dogs identified a SNP associated with development of CMCT in the GNAI2 gene (p = 2.2x10(-16)), introducing an alternative splice form of this gene resulting in a truncated protein. In addition, disease associated haplotypes harbouring the hyaluronidase genes HYAL1, HYAL2 and HYAL3 on cfa20 and HYAL4, SPAM1 and HYALP1 on cfa14 were identified as separate risk factors in European and US golden retrievers, respectively, suggesting that turnover of hyaluronan plays an important role in the development of CMCT.

  • 3.
    Ayllon, Fernando
    et al.
    Inst Marine Res, N-5024 Bergen, Norway..
    Kjaerner-Semb, Erik
    Inst Marine Res, N-5024 Bergen, Norway.;Univ Bergen, Dept Biol, Bergen, Norway..
    Furmanek, Tomasz
    Inst Marine Res, N-5024 Bergen, Norway..
    Wennevik, Vidar
    Inst Marine Res, N-5024 Bergen, Norway..
    Solberg, Monica F.
    Inst Marine Res, N-5024 Bergen, Norway..
    Dahle, Geir
    Inst Marine Res, N-5024 Bergen, Norway..
    Taranger, Geir Lasse
    Inst Marine Res, N-5024 Bergen, Norway..
    Glover, Kevin A.
    Inst Marine Res, N-5024 Bergen, Norway.;Univ Bergen, Dept Biol, Bergen, Norway..
    Almén, Markus Sällman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Edvardsen, Rolf B.
    Inst Marine Res, N-5024 Bergen, Norway..
    Wargelius, Anna
    Inst Marine Res, N-5024 Bergen, Norway..
    The vgll3 Locus Controls Age at Maturity in Wild and Domesticated Atlantic Salmon (Salmo salar L.) Males2015In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, no 11, article id e1005628Article in journal (Refereed)
    Abstract [en]

    Wild and domesticated Atlantic salmon males display large variation for sea age at sexual maturation, which varies between 1-5 years. Previous studies have uncovered a genetic predisposition for variation of age at maturity with moderate heritability, thus suggesting a polygenic or complex nature of this trait. The aim of this study was to identify associated genetic loci, genes and ultimately specific sequence variants conferring sea age at maturity in salmon. We performed a genome wide association study (GWAS) using a pool sequencing approach (20 individuals per river and phenotype) of male salmon returning to rivers as sexually mature either after one sea winter (2009) or three sea winters (2011) in six rivers in Norway. The study revealed one major selective sweep, which covered 76 significant SNPs in which 74 were found in a 370 kb region of chromosome 25. Genotyping other smolt year classes of wild and domesticated salmon confirmed this finding. Genotyping domesticated fish narrowed the haplotype region to four SNPs covering 2386 bp, containing the vgll3 gene, including two missense mutations explaining 33-36% phenotypic variation. A single locus was found to have a highly significant role in governing sea age at maturation in this species. The SNPs identified may be both used as markers to guide breeding for late maturity in salmon aquaculture and in monitoring programs of wild salmon. Interestingly, a SNP in proximity of the VGLL3 gene in humans (Homo sapiens), has previously been linked to age at puberty suggesting a conserved mechanism for timing of puberty in vertebrates.

  • 4. Bell, Jordana T
    et al.
    Tsai, Pei-Chien
    Yang, Tsun-Po
    Pidsley, Ruth
    Nisbet, James
    Glass, Daniel
    Mangino, Massimo
    Zhai, Guangju
    Zhang, Feng
    Valdes, Ana
    Shin, So-Youn
    Dempster, Emma L
    Murray, Robin M
    Grundberg, Elin
    Hedman, Asa K
    Nica, Alexandra
    Small, Kerrin S
    Dermitzakis, Emmanouil T
    McCarthy, Mark I
    Mill, Jonathan
    Spector, Tim D
    Deloukas, Panos
    Epigenome-wide scans identify differentially methylated regions for age and age-related phenotypes in a healthy ageing population.2012In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 8, no 4Article in journal (Refereed)
    Abstract [en]

    Age-related changes in DNA methylation have been implicated in cellular senescence and longevity, yet the causes and functional consequences of these variants remain unclear. To elucidate the role of age-related epigenetic changes in healthy ageing and potential longevity, we tested for association between whole-blood DNA methylation patterns in 172 female twins aged 32 to 80 with age and age-related phenotypes. Twin-based DNA methylation levels at 26,690 CpG-sites showed evidence for mean genome-wide heritability of 18%, which was supported by the identification of 1,537 CpG-sites with methylation QTLs in cis at FDR 5%. We performed genome-wide analyses to discover differentially methylated regions (DMRs) for sixteen age-related phenotypes (ap-DMRs) and chronological age (a-DMRs). Epigenome-wide association scans (EWAS) identified age-related phenotype DMRs (ap-DMRs) associated with LDL (STAT5A), lung function (WT1), and maternal longevity (ARL4A, TBX20). In contrast, EWAS for chronological age identified hundreds of predominantly hyper-methylated age DMRs (490 a-DMRs at FDR 5%), of which only one (TBX20) was also associated with an age-related phenotype. Therefore, the majority of age-related changes in DNA methylation are not associated with phenotypic measures of healthy ageing in later life. We replicated a large proportion of a-DMRs in a sample of 44 younger adult MZ twins aged 20 to 61, suggesting that a-DMRs may initiate at an earlier age. We next explored potential genetic and environmental mechanisms underlying a-DMRs and ap-DMRs. Genome-wide overlap across cis-meQTLs, genotype-phenotype associations, and EWAS ap-DMRs identified CpG-sites that had cis-meQTLs with evidence for genotype-phenotype association, where the CpG-site was also an ap-DMR for the same phenotype. Monozygotic twin methylation difference analyses identified one potential environmentally-mediated ap-DMR associated with total cholesterol and LDL (CSMD1). Our results suggest that in a small set of genes DNA methylation may be a candidate mechanism of mediating not only environmental, but also genetic effects on age-related phenotypes.

  • 5.
    Brandis, Gerrit
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hughes, Diarmaid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    The Selective Advantage of Synonymous Codon Usage Bias in Salmonella2016In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 12, no 3, article id e1005926Article in journal (Refereed)
    Abstract [en]

    The genetic code in mRNA is redundant, with 61 sense codons translated into 20 different amino acids. Individual amino acids are encoded by up to six different codons but within codon families some are used more frequently than others. This phenomenon is referred to as synonymous codon usage bias. The genomes of free-living unicellular organisms such as bacteria have an extreme codon usage bias and the degree of bias differs between genes within the same genome. The strong positive correlation between codon usage bias and gene expression levels in many microorganisms is attributed to selection for translational efficiency. However, this putative selective advantage has never been measured in bacteria and theoretical estimates vary widely. By systematically exchanging optimal codons for synonymous codons in the tuf genes we quantified the selective advantage of biased codon usage in highly expressed genes to be in the range 0.2–4.2 x 10−4 per codon per generation. These data quantify for the first time the potential for selection on synonymous codon choice to drive genome-wide sequence evolution in bacteria, and in particular to optimize the sequences of highly expressed genes. This quantification may have predictive applications in the design of synthetic genes and for heterologous gene expression in biotechnology.

  • 6.
    Choi, Seung Hoan
    et al.
    Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA.;Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA.;Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA..
    Ruggiero, Daniela
    CNR, Inst Genet & Biophys, Naples, Italy..
    Sorice, Rossella
    CNR, Inst Genet & Biophys, Naples, Italy..
    Song, Ci
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Natl Heart Lung & Blood Inst Framingham Heart Stu, Populat Sci Branch, Framingham, MA USA.;Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Nutile, Teresa
    CNR, Inst Genet & Biophys, Naples, Italy..
    Smith, Albert Vernon
    Iceland Heart Assoc, Kopavogur, Iceland.;Univ Iceland, Reykjavik, Iceland..
    Concas, Maria Pina
    CNR, Inst Populat Genet, Sassari, Italy..
    Traglia, Michela
    Ist Sci San Raffaele, Div Genet & Cell Biol, I-20132 Milan, Italy..
    Barbieri, Caterina
    Ist Sci San Raffaele, Div Genet & Cell Biol, I-20132 Milan, Italy..
    Ndiaye, Ndeye Coumba
    Univ Lorraine, Fac Pharm, UMR INSERM U1122, IGE PCV Interact Gene Environm Physiopathol Cardi, Nancy, France..
    Stathopoulou, Maria G.
    Univ Lorraine, Fac Pharm, UMR INSERM U1122, IGE PCV Interact Gene Environm Physiopathol Cardi, Nancy, France..
    Lagou, Vasiliki
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Maestrale, Giovanni Battista
    CNR, Inst Populat Genet, Sassari, Italy..
    Sala, Cinzia
    Ist Sci San Raffaele, Div Genet & Cell Biol, I-20132 Milan, Italy..
    Debette, Stephanie
    Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA.;Bordeaux Univ Hosp, Dept Neurol, Bordeaux, France.;INSERM, U897, Bordeaux, France..
    Kovacs, Peter
    Univ Leipzig, IFB Adipos Dis, D-04109 Leipzig, Germany..
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Lamont, John
    Randox Labs, Crumlin, Ireland..
    Fitzgerald, Peter
    Randox Labs, Crumlin, Ireland..
    Toenjes, Anke
    Univ Leipzig, Dept Med, D-04109 Leipzig, Germany..
    Gudnason, Vilmundur
    Iceland Heart Assoc, Kopavogur, Iceland.;Univ Iceland, Reykjavik, Iceland..
    Toniolo, Daniela
    Ist Sci San Raffaele, Div Genet & Cell Biol, I-20132 Milan, Italy..
    Pirastu, Mario
    CNR, Inst Populat Genet, Sassari, Italy..
    Bellenguez, Celine
    Inst Pasteur, F-59019 Lille, France.;INSEM, U744, Lille, France.;Univ Lille Nord France, Lille, France..
    Vasan, Ramachandran S.
    Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA.;Boston Univ, Sch Med, Dept Med, Sect Prevent Med & Epidemiol, Boston, MA 02215 USA.;Boston Univ, Sch Publ Hlth, Boston, MA 02215 USA..
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Leutenegger, Anne-Louise
    INSERM, U946, Paris, France.;Univ Paris Diderot, Sorbonne Paris Cite, IUH, UMR S 946, Paris, France..
    Johnson, Andrew D.
    Natl Heart Lung & Blood Inst Framingham Heart Stu, Populat Sci Branch, Framingham, MA USA..
    DeStefano, Anita L.
    Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA.;Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA.;Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA..
    Visvikis-Siest, Sophie
    Univ Lorraine, Fac Pharm, UMR INSERM U1122, IGE PCV Interact Gene Environm Physiopathol Cardi, Nancy, France..
    Seshadri, Sudha
    Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA.;Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA..
    Ciullo, Marina
    CNR, Inst Genet & Biophys, Naples, Italy..
    Six Novel Loci Associated with Circulating VEGF Levels Identified by a Meta-analysis of Genome-Wide Association Studies2016In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 12, no 2, article id e1005874Article in journal (Refereed)
    Abstract [en]

    Vascular endothelial growth factor (VEGF) is an angiogenic and neurotrophic factor, secreted by endothelial cells, known to impact various physiological and disease processes from cancer to cardiovascular disease and to be pharmacologically modifiable. We sought to identify novel loci associated with circulating VEGF levels through a genome-wide association meta-analysis combining data from European-ancestry individuals and using a dense variant map from 1000 genomes imputation panel. Six discovery cohorts including 13,312 samples were analyzed, followed by in-silico and de-novo replication studies including an additional 2,800 individuals. A total of 10 genome-wide significant variants were identified at 7 loci. Four were novel loci (5q14.3, 10q21.3, 16q24.2 and 18q22.3) and the leading variants at these loci were rs114694170 (MEF2C, P = 6.79x10(-13)), rs74506613 (JMJD1C, P = 1.17x10(-19)), rs4782371 (ZFPM1, P = 1.59x10(-9)) and rs2639990 (ZADH2, P = 1.72x10(-8)), respectively. We also identified two new independent variants (rs34528081, VEGFA, P = 1.52x10(-18); rs7043199, VLDLR-AS1, P = 5.12x10(-14)) at the 3 previously identified loci and strengthened the evidence for the four previously identified SNPs (rs6921438, LOC100132354, P = 7.39x10(-1467); rs1740073, C6orf223, P = 2.34x10(-17); rs6993770, ZFPM2, P = 2.44x10(-60); rs2375981, KCNV2, P = 1.48x10(-100)). These variants collectively explained up to 52% of the VEGF phenotypic variance. We explored biological links between genes in the associated loci using Ingenuity Pathway Analysis that emphasized their roles in embryonic development and function. Gene set enrichment analysis identified the ERK5 pathway as enriched in genes containing VEGF associated variants. eQTL analysis showed, in three of the identified regions, variants acting as both cis and trans eQTLs for multiple genes. Most of these genes, as well as some of those in the associated loci, were involved in platelet biogenesis and functionality, suggesting the importance of this process in regulation of VEGF levels. This work also provided new insights into the involvement of genes implicated in various angiogenesis related pathologies in determining circulating VEGF levels. The understanding of the molecular mechanisms by which the identified genes affect circulating VEGF levels could be important in the development of novel VEGF-related therapies for such diseases.

  • 7.
    Clement, Yves
    et al.
    Montpellier SupAgro, UMR AGAP, Montpellier, France.;Univ Montpellier, CNRS IRD EPHE, UMR ISEM 5554, Montpellier, France.;PSL Res Univ, Ecole Normale Super, CNRS, IBENS,INSERM, Paris, France..
    Sarah, Gautier
    INRA, UMR AGAP, Montpellier, France.;SouthGreen Platform, Montpellier, France..
    Holtz, Yan
    Montpellier SupAgro, UMR AGAP, Montpellier, France..
    Homa, Felix
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab. SouthGreen Platform, Montpellier, France..
    Pointet, Stephanie
    SouthGreen Platform, Montpellier, France.;CIRAD, UMR AGAP, Montpellier, France.;ALCEDIAG CNRS Sys2Diag FRE3690, Biol Complex Syst Modelling & Engn Diag, Montpellier, France..
    Contreras, Sandy
    SouthGreen Platform, Montpellier, France.;GenoScreen, Lille, France..
    Nabholz, Benoit
    Univ Montpellier, CNRS IRD EPHE, UMR ISEM 5554, Montpellier, France..
    Sabot, Francois
    SouthGreen Platform, Montpellier, France.;IRD, UMR DIADE, Montpellier, France..
    Saune, Laure
    INRA, CBGP UMR1062, Montferrier Sur Lez, France..
    Ardisson, Morgane
    INRA, UMR AGAP, Montpellier, France..
    Bacilieri, Roberto
    INRA, UMR AGAP, Montpellier, France..
    Besnard, Guillaume
    Univ Toulouse III, CNRS ENSFEA IRD, UMR EDB 5174, Toulouse, France..
    Berger, Angelique
    CIRAD, UMR AGAP, Montpellier, France..
    Cardi, Celine
    CIRAD, UMR AGAP, Montpellier, France..
    De Bellis, Fabien
    CIRAD, UMR AGAP, Montpellier, France..
    Fouet, Olivier
    CIRAD, UMR AGAP, Montpellier, France..
    Jourda, Cyril
    CIRAD, UMR AGAP, Montpellier, France.;CIRAD, UMR PVBMT, St Pierre, Reunion, France..
    Khadari, Bouchaib
    INRA, UMR AGAP, Montpellier, France..
    Lanaud, Claire
    CIRAD, UMR AGAP, Montpellier, France..
    Leroy, Thierry
    CIRAD, UMR AGAP, Montpellier, France..
    Pot, David
    Sauvage, Christopher
    INRA, GAFL UR1052, Montfavet, France..
    Scarcelli, Nora
    IRD, UMR DIADE, Montpellier, France..
    Tregear, James
    IRD, UMR DIADE, Montpellier, France..
    Vigouroux, Yves
    IRD, UMR DIADE, Montpellier, France..
    Yahiaoui, Nabila
    CIRAD, UMR AGAP, Montpellier, France..
    Ruiz, Manuel
    SouthGreen Platform, Montpellier, France.;CIRAD, UMR AGAP, Montpellier, France..
    Santoni, Sylvain
    INRA, UMR AGAP, Montpellier, France..
    Labouisse, Jean-Pierre
    CIRAD, UMR AGAP, Montpellier, France..
    Pham, Jean-Louis
    IRD, UMR DIADE, Montpellier, France..
    David, Jacques
    Montpellier SupAgro, UMR AGAP, Montpellier, France..
    Glemin, Sylvain
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution. Univ Montpellier.
    Evolutionary forces affecting synonymous variations in plant genomes2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 5, article id e1006799Article in journal (Refereed)
    Abstract [en]

    Base composition is highly variable among and within plant genomes, especially at third codon positions, ranging from GC-poor and homogeneous species to GC-rich and highly heterogeneous ones (particularly Monocots). Consequently, synonymous codon usage is biased in most species, even when base composition is relatively homogeneous. The causes of these variations are still under debate, with three main forces being possibly involved: mutational bias, selection and GC-biased gene conversion (gBGC). So far, both selection and gBGC have been detected in some species but how their relative strength varies among and within species remains unclear. Population genetics approaches allow to jointly estimating the intensity of selection, gBGC and mutational bias. We extended a recently developed method and applied it to a large population genomic dataset based on transcriptome sequencing of 11 angiosperm species spread across the phylogeny. We found that at synonymous positions, base composition is far from mutation-drift equilibrium in most genomes and that gBGC is a widespread and stronger process than selection. gBGC could strongly contribute to base composition variation among plant species, implying that it should be taken into account in plant genome analyses, especially for GC-rich ones.

  • 8. Decker, Jared E.
    et al.
    McKay, Stephanie D.
    Rolf, Megan M.
    Kim, JaeWoo
    Molina Alcala, Antonio
    Sonstegard, Tad S.
    Hanotte, Olivier
    Götherström, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Seabury, Christopher M.
    Praharani, Lisa
    Babar, Masroor Ellahi
    de Almeida Regitano, Luciana Correia
    Yildiz, Mehmet Ali
    Heaton, Michael P.
    Liu, Wan-Sheng
    Lei, Chu-Zhao
    Reecy, James M.
    Saif-Ur-Rehman, Muhammad
    Schnabel, Robert D.
    Taylor, Jeremy F.
    Worldwide Patterns of Ancestry, Divergence, and Admixture in Domesticated Cattle2014In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 3, p. e1004254-Article in journal (Refereed)
    Abstract [en]

    The domestication and development of cattle has considerably impacted human societies, but the histories of cattle breeds and populations have been poorly understood especially for African, Asian, and American breeds. Using genotypes from 43,043 autosomal single nucleotide polymorphism markers scored in 1,543 animals, we evaluate the population structure of 134 domesticated bovid breeds. Regardless of the analytical method or sample subset, the three major groups of Asian indicine, Eurasian taurine, and African taurine were consistently observed. Patterns of geographic dispersal resulting from co-migration with humans and exportation are recognizable in phylogenetic networks. All analytical methods reveal patterns of hybridization which occurred after divergence. Using 19 breeds, we map the cline of indicine introgression into Africa. We infer that African taurine possess a large portion of wild African auroch ancestry, causing their divergence from Eurasian taurine. We detect exportation patterns in Asia and identify a cline of Eurasian taurine/indicine hybridization in Asia. We also identify the influence of species other than Bos taurus taurus and B. t. indicus in the formation of Asian breeds. We detect the pronounced influence of Shorthorn cattle in the formation of European breeds. Iberian and Italian cattle possess introgression from African taurine. American Criollo cattle originate from Iberia, and not directly from Africa with African ancestry inherited via Iberian ancestors. Indicine introgression into American cattle occurred in the Americas, and not Europe. We argue that cattle migration, movement and trading followed by admixture have been important forces in shaping modern bovine genomic variation.

  • 9. Folkersen, Lasse
    et al.
    Fauman, Eric
    Sabater-Lleal, Maria
    Strawbridge, Rona J
    Frånberg, Mattias
    Sennblad, Bengt
    Baldassarre, Damiano
    Veglia, Fabrizio
    Humphries, Steve E
    Rauramaa, Rainer
    de Faire, Ulf
    Smit, Andries J
    Giral, Philippe
    Kurl, Sudhir
    Mannarino, Elmo
    Enroth, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Johansson, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bosdotter Enroth, Sofia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Gustafsson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lind, Lars
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Lindgren, Cecilia
    Morris, Andrew P
    Giedraitis, Vilmantas
    Silveira, Angela
    Franco-Cereceda, Anders
    Tremoli, Elena
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Brunak, Søren
    Eriksson, Per
    Ziemek, Daniel
    Hamsten, Anders
    Mälarstig, Anders
    Mapping of 79 loci for 83 plasma protein biomarkers in cardiovascular disease2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 4, article id e1006706Article in journal (Refereed)
    Abstract [en]

    Recent advances in highly multiplexed immunoassays have allowed systematic large-scale measurement of hundreds of plasma proteins in large cohort studies. In combination with genotyping, such studies offer the prospect to 1) identify mechanisms involved with regulation of protein expression in plasma, and 2) determine whether the plasma proteins are likely to be causally implicated in disease. We report here the results of genome-wide association (GWA) studies of 83 proteins considered relevant to cardiovascular disease (CVD), measured in 3,394 individuals with multiple CVD risk factors. We identified 79 genome-wide significant (p<5e-8) association signals, 55 of which replicated at P<0.0007 in separate validation studies (n = 2,639 individuals). Using automated text mining, manual curation, and network-based methods incorporating information on expression quantitative trait loci (eQTL), we propose plausible causal mechanisms for 25 trans-acting loci, including a potential post-translational regulation of stem cell factor by matrix metalloproteinase 9 and receptor-ligand pairs such as RANK-RANK ligand. Using public GWA study data, we further evaluate all 79 loci for their causal effect on coronary artery disease, and highlight several potentially causal associations. Overall, a majority of the plasma proteins studied showed evidence of regulation at the genetic level. Our results enable future studies of the causal architecture of human disease, which in turn should aid discovery of new drug targets.

  • 10. Forsberg, Simon K G
    et al.
    Andreatta, Matthew E
    Huang, Xin-Yuan
    Danku, John
    Salt, David E
    Carlborg, Örjan
    SLU.
    The Multi-allelic Genetic Architecture of a Variance-Heterogeneity Locus for Molybdenum Concentration in Leaves Acts as a Source of Unexplained Additive Genetic Variance.2015In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, no 11Article in journal (Refereed)
    Abstract [en]

    Genome-wide association (GWA) analyses have generally been used to detect individual loci contributing to the phenotypic diversity in a population by the effects of these loci on the trait mean. More rarely, loci have also been detected based on variance differences between genotypes. Several hypotheses have been proposed to explain the possible genetic mechanisms leading to such variance signals. However, little is known about what causes these signals, or whether this genetic variance-heterogeneity reflects mechanisms of importance in natural populations. Previously, we identified a variance-heterogeneity GWA (vGWA) signal for leaf molybdenum concentrations in Arabidopsis thaliana. Here, fine-mapping of this association reveals that the vGWA emerges from the effects of three independent genetic polymorphisms that all are in strong LD with the markers displaying the genetic variance-heterogeneity. By revealing the genetic architecture underlying this vGWA signal, we uncovered the molecular source of a significant amount of hidden additive genetic variation or "missing heritability". Two of the three polymorphisms underlying the genetic variance-heterogeneity are promoter variants for Molybdate transporter 1 (MOT1), and the third a variant located ~25 kb downstream of this gene. A fourth independent association was also detected ~600 kb upstream of MOT1. Use of a T-DNA knockout allele highlights Copper Transporter 6; COPT6 (AT2G26975) as a strong candidate gene for this association. Our results show that an extended LD across a complex locus including multiple functional alleles can lead to a variance-heterogeneity between genotypes in natural populations. Further, they provide novel insights into the genetic regulation of ion homeostasis in A. thaliana, and empirically confirm that variance-heterogeneity based GWA methods are a valuable tool to detect novel associations of biological importance in natural populations.

  • 11.
    Gomez-Velazquez, Melisa
    et al.
    CNIC, Madrid, Spain..
    Badia-Careaga, Claudio
    CNIC, Madrid, Spain..
    Victoria Lechuga-Vieco, Ana
    CNIC, Madrid, Spain..
    Nieto-Arellano, Rocio
    CNIC, Madrid, Spain..
    Tena, Juan J.
    Univ Pablo de Olavide Junta de Andalucia, CSIC, CABD, Seville, Spain..
    Rollan, Isabel
    CNIC, Madrid, Spain..
    Alvarez, Alba
    CNIC, Madrid, Spain..
    Torroja, Carlos
    CNIC, Madrid, Spain..
    Caceres, Eva F.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab. CNIC, Madrid, Spain..
    Roy, Anna
    Hosp Sick Children, Translat Med, Toronto, ON, Canada.;Univ Toronto, Dept Mol Genet, Toronto, ON, Canada..
    Galjart, Niels
    Erasmus MC, Dept Cell Biol & Genet, Rotterdam, Netherlands..
    Delgado-Olguin, Paul
    Hosp Sick Children, Translat Med, Toronto, ON, Canada.;Univ Toronto, Dept Mol Genet, Toronto, ON, Canada.;Heart & Stroke Richard Lewar Ctr Excellence, Toronto, ON, Canada..
    Sanchez-Cabo, Fatima
    CNIC, Madrid, Spain..
    Antonio Enriquez, Jose
    CNIC, Madrid, Spain..
    Luis Gomez-Skarmeta, Jose
    Univ Pablo de Olavide Junta de Andalucia, CSIC, CABD, Seville, Spain..
    Manzanares, Miguel
    CNIC, Madrid, Spain..
    CTCF counter-regulates cardiomyocyte development and maturation programs in the embryonic heart2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 8, article id e1006985Article in journal (Refereed)
    Abstract [en]

    Cardiac progenitors are specified early in development and progressively differentiate and mature into fully functional cardiomyocytes. This process is controlled by an extensively studied transcriptional program. However, the regulatory events coordinating the progression of such program from development to maturation are largely unknown. Here, we show that the genome organizer CTCF is essential for cardiogenesis and that it mediates genomic interactions to coordinate cardiomyocyte differentiation and maturation in the developing heart. Inactivation of Ctcf in cardiac progenitor cells and their derivatives in vivo during development caused severe cardiac defects and death at embryonic day 12.5. Genome wide expression analysis in Ctcf mutant hearts revealed that genes controlling mitochondrial function and protein production, required for cardiomyocyte maturation, were upregulated. However, mitochondria from mutant cardiomyocytes do not mature properly. In contrast, multiple development regulatory genes near predicted heart enhancers, including genes in the IrxA cluster, were downregulated in Ctcf mutants, suggesting that CTCF promotes cardiomyocyte differentiation by facilitating enhancer-promoter interactions. Accordingly, loss of CTCF disrupts gene expression and chromatin interactions as shown by chromatin conformation capture followed by deep sequencing. Furthermore, CRISPR-mediated deletion of an intergenic CTCF site within the IrxA cluster alters gene expression in the developing heart. Thus, CTCF mediates local regulatory interactions to coordinate transcriptional programs controlling transitions in morphology and function during heart development.

  • 12. Graff, Mariaelisa
    et al.
    Scott, Robert A
    Justice, Anne E
    Young, Kristin L
    Feitosa, Mary F
    Barata, Llilda
    Winkler, Thomas W
    Chu, Audrey Y
    Mahajan, Anubha
    Hadley, David
    Xue, Luting
    Workalemahu, Tsegaselassie
    Heard-Costa, Nancy L
    den Hoed, Marcel
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.
    Ahluwalia, Tarunveer S
    Qi, Qibin
    Ngwa, Julius S
    Renström, Frida
    Quaye, Lydia
    Eicher, John D
    Hayes, James E
    Cornelis, Marilyn
    Kutalik, Zoltan
    Lim, Elise
    Luan, Jian'an
    Huffman, Jennifer E
    Zhang, Weihua
    Zhao, Wei
    Griffin, Paula J
    Haller, Toomas
    Ahmad, Shafqat
    Marques-Vidal, Pedro M
    Bien, Stephanie
    Yengo, Loic
    Teumer, Alexander
    Smith, Albert Vernon
    Kumari, Meena
    Harder, Marie Neergaard
    Justesen, Johanne Marie
    Kleber, Marcus E
    Hollensted, Mette
    Lohman, Kurt
    Rivera, Natalia V
    Whitfield, John B
    Zhao, Jing Hua
    Stringham, Heather M
    Lyytikäinen, Leo-Pekka
    Huppertz, Charlotte
    Willemsen, Gonneke
    Peyrot, Wouter J
    Wu, Ying
    Kristiansson, Kati
    Demirkan, Ayse
    Fornage, Myriam
    Hassinen, Maija
    Bielak, Lawrence F
    Cadby, Gemma
    Tanaka, Toshiko
    Mägi, Reedik
    van der Most, Peter J
    Jackson, Anne U
    Bragg-Gresham, Jennifer L
    Vitart, Veronique
    Marten, Jonathan
    Navarro, Pau
    Bellis, Claire
    Pasko, Dorota
    Johansson, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Snitker, Søren
    Cheng, Yu-Ching
    Eriksson, Joel
    Lim, Unhee
    Aadahl, Mette
    Adair, Linda S
    Amin, Najaf
    Balkau, Beverley
    Auvinen, Juha
    Beilby, John
    Bergman, Richard N
    Bergmann, Sven
    Bertoni, Alain G
    Blangero, John
    Bonnefond, Amélie
    Bonnycastle, Lori L
    Borja, Judith B
    Brage, Søren
    Busonero, Fabio
    Buyske, Steve
    Campbell, Harry
    Chines, Peter S
    Collins, Francis S
    Corre, Tanguy
    Smith, George Davey
    Delgado, Graciela E
    Dueker, Nicole
    Dörr, Marcus
    Ebeling, Tapani
    Eiriksdottir, Gudny
    Esko, Tõnu
    Faul, Jessica D
    Fu, Mao
    Færch, Kristine
    Gieger, Christian
    Gläser, Sven
    Gong, Jian
    Gordon-Larsen, Penny
    Grallert, Harald
    Grammer, Tanja B
    Grarup, Niels
    van Grootheest, Gerard
    Harald, Kennet
    Hastie, Nicholas D
    Havulinna, Aki S
    Hernandez, Dena
    Hindorff, Lucia
    Hocking, Lynne J
    Holmens, Oddgeir L
    Holzapfel, Christina
    Hottenga, Jouke Jan
    Huang, Jie
    Huang, Tao
    Hui, Jennie
    Huth, Cornelia
    Hutri-Kähönen, Nina
    James, Alan L
    Jansson, John-Olov
    Jhun, Min A
    Juonala, Markus
    Kinnunen, Leena
    Koistinen, Heikki A
    Kolcic, Ivana
    Komulainen, Pirjo
    Kuusisto, Johanna
    Kvaløy, Kirsti
    Kähönen, Mika
    Lakka, Timo A
    Launer, Lenore J
    Lehne, Benjamin
    Lindgren, Cecilia M
    Lorentzon, Mattias
    Luben, Robert
    Marre, Michel
    Milaneschi, Yuri
    Monda, Keri L
    Montgomery, Grant W
    De Moor, Marleen H M
    Mulas, Antonella
    Müller-Nurasyid, Martina
    Musk, A W
    Männikkö, Reija
    Männistö, Satu
    Narisu, Narisu
    Nauck, Matthias
    Nettleton, Jennifer A
    Nolte, Ilja M
    Oldehinkel, Albertine J
    Olden, Matthias
    Ong, Ken K
    Padmanabhan, Sandosh
    Paternoster, Lavinia
    Perez, Jeremiah
    Perola, Markus
    Peters, Annette
    Peters, Ulrike
    Peyser, Patricia A
    Prokopenko, Inga
    Puolijoki, Hannu
    Raitakari, Olli T
    Rankinen, Tuomo
    Rasmussen-Torvik, Laura J
    Rawal, Rajesh
    Ridker, Paul M
    Rose, Lynda M
    Rudan, Igor
    Sarti, Cinzia
    Sarzynski, Mark A
    Savonen, Kai
    Scott, William R
    Sanna, Serena
    Shuldiner, Alan R
    Sidney, Steve
    Silbernagel, Günther
    Smith, Blair H
    Smith, Jennifer A
    Snieder, Harold
    Stančáková, Alena
    Sternfeld, Barbara
    Swift, Amy J
    Tammelin, Tuija
    Tan, Sian-Tsung
    Thorand, Barbara
    Thuillier, Dorothée
    Vandenput, Liesbeth
    Vestergaard, Henrik
    van Vliet-Ostaptchouk, Jana V
    Vohl, Marie-Claude
    Völker, Uwe
    Waeber, Gérard
    Walker, Mark
    Wild, Sarah
    Wong, Andrew
    Wright, Alan F
    Zillikens, M Carola
    Zubair, Niha
    Haiman, Christopher A
    Lemarchand, Loic
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Ohlsson, Claes
    Hofman, Albert
    Rivadeneira, Fernando
    Uitterlinden, André G
    Pérusse, Louis
    Wilson, James F
    Hayward, Caroline
    Polasek, Ozren
    Cucca, Francesco
    Hveem, Kristian
    Hartman, Catharina A
    Tönjes, Anke
    Bandinelli, Stefania
    Palmer, Lyle J
    Kardia, Sharon L R
    Rauramaa, Rainer
    Sørensen, Thorkild I A
    Tuomilehto, Jaakko
    Salomaa, Veikko
    Penninx, Brenda W J H
    de Geus, Eco J C
    Boomsma, Dorret I
    Lehtimäki, Terho
    Mangino, Massimo
    Laakso, Markku
    Bouchard, Claude
    Martin, Nicholas G
    Kuh, Diana
    Liu, Yongmei
    Linneberg, Allan
    März, Winfried
    Strauch, Konstantin
    Kivimäki, Mika
    Harris, Tamara B
    Gudnason, Vilmundur
    Völzke, Henry
    Qi, Lu
    Järvelin, Marjo-Riitta
    Chambers, John C
    Kooner, Jaspal S
    Froguel, Philippe
    Kooperberg, Charles
    Vollenweider, Peter
    Hallmans, Göran
    Hansen, Torben
    Pedersen, Oluf
    Metspalu, Andres
    Wareham, Nicholas J
    Langenberg, Claudia
    Weir, David R
    Porteous, David J
    Boerwinkle, Eric
    Chasman, Daniel I
    Abecasis, Gonçalo R
    Barroso, Inês
    McCarthy, Mark I
    Frayling, Timothy M
    O'Connell, Jeffrey R
    van Duijn, Cornelia M
    Boehnke, Michael
    Heid, Iris M
    Mohlke, Karen L
    Strachan, David P
    Fox, Caroline S
    Liu, Ching-Ti
    Hirschhorn, Joel N
    Klein, Robert J
    Johnson, Andrew D
    Borecki, Ingrid B
    Franks, Paul W
    North, Kari E
    Cupples, L Adrienne
    Loos, Ruth J F
    Kilpeläinen, Tuomas O
    Genome-wide physical activity interactions in adiposity: A meta-analysis of 200,452 adults.2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 4, article id e1006528Article in journal (Refereed)
    Abstract [en]

    Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.

  • 13. Guo, Ying
    et al.
    Gu, Xiaorong
    Sheng, Zheya
    Wang, Yanqiang
    Luo, Chenglong
    Liu, Ranran
    Qu, Hao
    Shu, Dingming
    Wen, Jie
    Crooijmans, Richard P M A
    Carlborg, Örjan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zhao, Yiqiang
    Hu, Xiaoxiang
    Li, Ning
    A Complex Structural Variation on Chromosome 27 Leads to the Ectopic Expression of HOXB8 and the Muffs and Beard Phenotype in Chickens2016In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 12, no 6, article id e1006071Article in journal (Refereed)
    Abstract [en]

    Muffs and beard (Mb) is a phenotype in chickens where groups of elongated feathers gather from both sides of the face (muffs) and below the beak (beard). It is an autosomal, incomplete dominant phenotype encoded by the Muffs and beard (Mb) locus. Here we use genome-wide association (GWA) analysis, linkage analysis, Identity-by-Descent (IBD) mapping, array-CGH, genome re-sequencing and expression analysis to show that the Mb allele causing the Mb phenotype is a derived allele where a complex structural variation (SV) on GGA27 leads to an altered expression of the gene HOXB8. This Mb allele was shown to be completely associated with the Mb phenotype in nine other independent Mb chicken breeds. The Mb allele differs from the wild-type mb allele by three duplications, one in tandem and two that are translocated to that of the tandem repeat around 1.70 Mb on GGA27. The duplications contain total seven annotated genes and their expression was tested during distinct stages of Mb morphogenesis. A continuous high ectopic expression of HOXB8 was found in the facial skin of Mb chickens, strongly suggesting that HOXB8 directs this regional feather-development. In conclusion, our results provide an interesting example of how genomic structural rearrangements alter the regulation of genes leading to novel phenotypes. Further, it again illustrates the value of utilizing derived phenotypes in domestic animals to dissect the genetic basis of developmental traits, herein providing novel insights into the likely role of HOXB8 in feather development and differentiation.

  • 14. Hunley, Keith
    et al.
    Dunn, Michael
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Languages, Department of Linguistics and Philology.
    Lindström, Eva
    Reesink, Ger
    Terrill, Angela
    Healy, Meghan E.
    Koki, George
    Friedlaender, Françoise R.
    Friedlaender, Jonathan S.
    Genetic and Linguistic Coevolution in Northern Island Melanesia2008In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 4, no 10Article in journal (Refereed)
    Abstract [en]

    Recent studies have detailed a remarkable degree of genetic and linguistic diversity in Northern Island Melanesia. Here we utilize that diversity to examine two models of genetic and linguistic coevolution. The first model predicts that genetic and linguistic correspondences formed following population splits and isolation at the time of early range expansions into the region. The second is analogous to the genetic model of isolation by distance, and it predicts that genetic and linguistic correspondences formed through continuing genetic and linguistic exchange between neighboring populations. We tested the predictions of the two models by comparing observed and simulated patterns of genetic variation, genetic and linguistic trees, and matrices of genetic, linguistic, and geographic distances. The data consist of 751 autosomal microsatellites and 108 structural linguistic features collected from 33 Northern Island Melanesian populations. The results of the tests indicate that linguistic and genetic exchange have erased any evidence of a splitting and isolation process that might have occurred early in the settlement history of the region. The correlation patterns are also inconsistent with the predictions of the isolation by distance coevolutionary process in the larger Northern Island Melanesian region, but there is strong evidence for the process in the rugged interior of the largest island in the region (New Britain). There we found some of the strongest recorded correlations between genetic, linguistic, and geographic distances. We also found that, throughout the region, linguistic features have generally been less likely to diffuse across population boundaries than genes. The results from our study, based on exceptionally fine-grained data, show that local genetic and linguistic exchange are likely to obscure evidence of the early history of a region, and that language barriers do not particularly hinder genetic exchange. In contrast, global patterns may emphasize more ancient demographic events, including population splits associated with the early colonization of major world regions. The coevolution of genes and languages has been a subject of enduring interest among geneticists and linguists. Progress has been limited by the available data and by the methods employed to compare patterns of genetic and linguistic variation. Here, we use high-quality data and novel methods to test two models of genetic and linguistic coevolution in Northern Island Melanesia, a region known for its complex history and remarkable biological and linguistic diversity. The first model predicts that congruent genetic and linguistic trees formed following serial population splits and isolation that occurred early in the settlement history of the region. The second model emphasizes the role of post-settlement exchange among neighboring groups in determining genetic and linguistic affinities. We rejected both models for the larger region, but found strong evidence for the post-settlement exchange model in the rugged interior of its largest island, where people have maintained close ties to their ancestral lands. The exchange (particularly genetic exchange) has obscured but not completely erased signals of early migrations into Island Melanesia, and such exchange has probably obscured early prehistory within other regions. In contrast, local exchange is less likely to have obscured evidence of population history at larger geographic scales.

  • 15.
    Klar, Joakim
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Piontek, Jörg
    Milatz, Susanne
    Tariq, Muhammad
    Jameel, Muhammad
    Breiderhoff, Tilman
    Schuster, Jens
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Fatima, Ambrin
    Asif, Maria
    Sher, Muhammad
    Mäbert, Katrin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Fromm, Anja
    Baig, Shahid M
    Günzel, Dorothee
    Dahl, Niklas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Altered paracellular cation permeability due to a rare CLDN10B variant causes anhidrosis and kidney damage2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 7, article id e1006897Article in journal (Refereed)
    Abstract [en]

    Claudins constitute the major component of tight junctions and regulate paracellular permeability of epithelia. Claudin-10 occurs in two major isoforms that form paracellular channels with ion selectivity. We report on two families segregating an autosomal recessive disorder characterized by generalized anhidrosis, severe heat intolerance and mild kidney failure. All affected individuals carry a rare homozygous missense mutation c.144C>G, p.(N48K) specific for the claudin-10b isoform. Immunostaining of sweat glands from patients suggested that the disease is associated with reduced levels of claudin-10b in the plasma membranes and in canaliculi of the secretory portion. Expression of claudin-10b N48K in a 3D cell model of sweat secretion indicated perturbed paracellular Na+ transport. Analysis of paracellular permeability revealed that claudin-10b N48K maintained cation over anion selectivity but with a reduced general ion conductance. Furthermore, freeze fracture electron microscopy showed that claudin-10b N48K was associated with impaired tight junction strand formation and altered cis-oligomer formation. These data suggest that claudin-10b N48K causes anhidrosis and our findings are consistent with a combined effect from perturbed TJ function and increased degradation of claudin-10b N48K in the sweat glands. Furthermore, affected individuals present with Mg2+ retention, secondary hyperparathyroidism and mild kidney failure that suggest a disturbed reabsorption of cations in the kidneys. These renal-derived features recapitulate several phenotypic aspects detected in mice with kidney specific loss of both claudin-10 isoforms. Our study adds to the spectrum of phenotypes caused by tight junction proteins and demonstrates a pivotal role for claudin-10b in maintaining paracellular Na+ permeability for sweat production and kidney function.

  • 16. Koskiniemi, Sanna
    et al.
    Garza-Sanchez, Fernando
    Sandegren, Linus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Webb, Julia S.
    Braaten, Bruce A.
    Poole, Stephen J.
    Andersson, Dan I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hayes, Christopher S.
    Low, David A.
    Selection of Orphan Rhs Toxin Expression in Evolved Salmonella enterica Serovar Typhimurium2014In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 3, p. e1004255-Article in journal (Refereed)
    Abstract [en]

    Clonally derived bacterial populations exhibit significant genotypic and phenotypic diversity that contribute to fitness in rapidly changing environments. Here, we show that serial passage of Salmonella enterica serovar Typhimurium LT2 (StLT2) in broth, or within a mouse host, results in selection of an evolved population that inhibits the growth of ancestral cells by direct contact. Cells within each evolved population gain the ability to express and deploy a cryptic "orphan" toxin encoded within the rearrangement hotspot (rhs) locus. The Rhs orphan toxin is encoded by a gene fragment located downstream of the "main" rhs gene in the ancestral strain StLT2. The Rhs orphan coding sequence is linked to an immunity gene, which encodes an immunity protein that specifically blocks Rhs orphan toxin activity. Expression of the Rhs orphan immunity protein protects ancestral cells from the evolved lineages, indicating that orphan toxin activity is responsible for the observed growth inhibition. Because the Rhs orphan toxin is encoded by a fragmented reading frame, it lacks translation initiation and protein export signals. We provide evidence that evolved cells undergo recombination between the main rhs gene and the rhs orphan toxin gene fragment, yielding a fusion that enables expression and delivery of the orphan toxin. In this manner, rhs locus rearrangement provides a selective advantage to a subpopulation of cells. These observations suggest that rhs genes play important roles in intra-species competition and bacterial evolution.

  • 17. Lachowiec, Jennifer
    et al.
    Shen, Xia
    Queitsch, Christine
    Carlborg, Örjan
    SLU.
    A Genome-Wide Association Analysis Reveals Epistatic Cancellation of Additive Genetic Variance for Root Length in Arabidopsis thaliana.2015In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, no 9Article in journal (Refereed)
    Abstract [en]

    Efforts to identify loci underlying complex traits generally assume that most genetic variance is additive. Here, we examined the genetics of Arabidopsis thaliana root length and found that the genomic narrow-sense heritability for this trait in the examined population was statistically zero. The low amount of additive genetic variance that could be captured by the genome-wide genotypes likely explains why no associations to root length could be found using standard additive-model-based genome-wide association (GWA) approaches. However, as the broad-sense heritability for root length was significantly larger, and primarily due to epistasis, we also performed an epistatic GWA analysis to map loci contributing to the epistatic genetic variance. Four interacting pairs of loci were revealed, involving seven chromosomal loci that passed a standard multiple-testing corrected significance threshold. The genotype-phenotype maps for these pairs revealed epistasis that cancelled out the additive genetic variance, explaining why these loci were not detected in the additive GWA analysis. Small population sizes, such as in our experiment, increase the risk of identifying false epistatic interactions due to testing for associations with very large numbers of multi-marker genotypes in few phenotyped individuals. Therefore, we estimated the false-positive risk using a new statistical approach that suggested half of the associated pairs to be true positive associations. Our experimental evaluation of candidate genes within the seven associated loci suggests that this estimate is conservative; we identified functional candidate genes that affected root development in four loci that were part of three of the pairs. The statistical epistatic analyses were thus indispensable for confirming known, and identifying new, candidate genes for root length in this population of wild-collected A. thaliana accessions. We also illustrate how epistatic cancellation of the additive genetic variance explains the insignificant narrow-sense and significant broad-sense heritability by using a combination of careful statistical epistatic analyses and functional genetic experiments.

  • 18.
    Li, He
    et al.
    Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, 825 NE 13th St, Oklahoma City, OK 73104 USA.;Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK USA.;Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA..
    Reksten, Tove Ragna
    Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, 825 NE 13th St, Oklahoma City, OK 73104 USA.;Univ Bergen, Dept Clin Sci, Broegelmann Res Lab, Bergen, Norway..
    Ice, John A.
    Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, 825 NE 13th St, Oklahoma City, OK 73104 USA..
    Kelly, Jennifer A.
    Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, 825 NE 13th St, Oklahoma City, OK 73104 USA..
    Adrianto, Indra
    Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, 825 NE 13th St, Oklahoma City, OK 73104 USA..
    Rasmussen, Astrid
    Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, 825 NE 13th St, Oklahoma City, OK 73104 USA..
    Wang, Shaofeng
    Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, 825 NE 13th St, Oklahoma City, OK 73104 USA..
    He, Bo
    Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, 825 NE 13th St, Oklahoma City, OK 73104 USA.;Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK USA..
    Grundahl, Kiely M.
    Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, 825 NE 13th St, Oklahoma City, OK 73104 USA..
    Glenn, Stuart B.
    Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, 825 NE 13th St, Oklahoma City, OK 73104 USA..
    Miceli-Richard, Corinne
    Univ Paris Sud, Hop Univ Paris Sud, AP HP, INSERM,U1012, Le Kremlin Bicetre, France..
    Bowman, Simon
    Univ Hosp Birmingham, Rheumatol Dept, Birmingham, W Midlands, England..
    Lester, Sue
    Queen Elizabeth Hosp, Adelaide, SA, Australia..
    Eriksson, Per
    Linkoping Univ, Dept Rheumatol Clin & Expt Med, Linkoping, Sweden..
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Brun, Johan G.
    Univ Bergen, Dept Clin Sci, Bergen, Norway.;Haukeland Hosp, Dept Rheumatol, Bergen, Norway..
    Goransson, Lasse G.
    Stavanger Univ Hosp, Dept Internal Med, Clin Immunol Unit, Stavanger, Norway..
    Harboe, Erna
    Stavanger Univ Hosp, Dept Internal Med, Clin Immunol Unit, Stavanger, Norway..
    Guthridge, Joel M.
    Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, 825 NE 13th St, Oklahoma City, OK 73104 USA..
    Kaufman, Kenneth M.
    Cincinnati Childrens Hosp Med Ctr, Div Rheurnatol, Cincinnati, OH 45229 USA.;US Dept Vet Affairs, Med Ctr, Cincinnati, OH USA..
    Kvarnstrom, Marika
    Karolinska Inst, Dept Med, Stockholm, Sweden..
    Graham, Deborah S. Cunninghame
    Kings Coll London, Dept Med & Mol Genet, London, England..
    Patel, Ketan
    Univ Minnesota, Sch Dent, Dept Dev & Surg Sci, Div Oral & Maxillofacial Surg, Minneapolis, MN 55455 USA.;North Mem Med Ctr, Dept Oral & Maxillofacial Surg, Robbinsdale, MN USA..
    Adler, Adam J.
    Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, 825 NE 13th St, Oklahoma City, OK 73104 USA..
    Farris, A. Darise
    Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, 825 NE 13th St, Oklahoma City, OK 73104 USA.;Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK USA..
    Brennan, Michael T.
    Carolinas Med Ctr, Dept Oral Med, Charlotte, NC 28203 USA..
    Chodosh, James
    Harvard Med Sch, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Boston, MA USA..
    Gopalakrishnan, Rajaram
    Univ Minnesota, Sch Dent, Dept Diagnost & Biol Sci, Div Oral Pathol, Minneapolis, MN 55455 USA..
    Weisman, Michael H.
    Cedars Sinai Med Ctr, Div Rheumatol, Los Angeles, CA 90048 USA..
    Venuturupalli, Swamy
    Cedars Sinai Med Ctr, Div Rheumatol, Los Angeles, CA 90048 USA..
    Wallace, Daniel J.
    Cedars Sinai Med Ctr, Div Rheumatol, Los Angeles, CA 90048 USA..
    Hefner, Kimberly S.
    Cedars Sinai Med Ctr, Div Rheumatol, Los Angeles, CA 90048 USA.;Hefner Eye Care & Opt Ctr, Oklahoma City, OK USA..
    Houston, Glen D.
    Univ Oklahoma, Coll Dent, Dept Oral & Maxillofacial Pathol, Oklahoma City, OK USA.;Heartland Pathol Consultants, Edmond, OK USA..
    Huang, Andrew J. W.
    Washington Univ, Dept Ophthalmol & Visual Sci, St Louis, MO 63130 USA..
    Hughes, Pamela J.
    Univ Minnesota, Sch Dent, Dept Dev & Surg Sci, Div Oral & Maxillofacial Surg, Minneapolis, MN 55455 USA..
    Lewis, David M.
    Univ Oklahoma, Coll Dent, Dept Oral & Maxillofacial Pathol, Oklahoma City, OK USA..
    Radfar, Lida
    Univ Oklahoma, Coll Dent, Oral Diagnosis & Radiol Dept, Oklahoma City, OK USA..
    Vista, Evan S.
    Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, 825 NE 13th St, Oklahoma City, OK 73104 USA.;Univ Santo Tomas Hosp, Manila, Philippines..
    Edgar, Contessa E.
    Oklahoma Baptist Univ, Biol Dept, Oklahoma City, OK USA..
    Rohrer, Michael D.
    Univ Minnesota, Sch Dent, Hard Tissue Res Lab, Minneapolis, MN 55455 USA..
    Stone, Donald U.
    Johns Hopkins Univ, Dept Ophthalmol, Baltimore, MD USA..
    Vyse, Timothy J.
    Kings Coll London, Dept Med & Mol Genet, London, England..
    Harley, John B.
    Cincinnati Childrens Hosp Med Ctr, Div Rheurnatol, Cincinnati, OH 45229 USA.;US Dept Vet Affairs, Med Ctr, Cincinnati, OH USA..
    Gaffney, Patrick M.
    Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, 825 NE 13th St, Oklahoma City, OK 73104 USA..
    James, Judith A.
    Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, 825 NE 13th St, Oklahoma City, OK 73104 USA.;Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK USA.;Univ Oklahoma, Hlth Sci Ctr, Dept Med, Oklahoma City, OK USA..
    Turner, Sean
    Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, 825 NE 13th St, Oklahoma City, OK 73104 USA..
    Alevizos, Ilias
    Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA..
    Anaya, Juan-Manuel
    Univ Rosario, Cente Autoimmune Dis Res, Bogota, Colombia..
    Rhodus, Nelson L.
    Univ Minnesota, Sch Dent, Dept Oral Surg, Minneapolis, MN 55455 USA..
    Segal, Barbara M.
    Univ Minnesota, Sch Med, Div Rheumatol, Minneapolis, MN 55455 USA..
    Montgomery, Courtney G.
    Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, 825 NE 13th St, Oklahoma City, OK 73104 USA..
    Scofield, R. Hal
    Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, 825 NE 13th St, Oklahoma City, OK 73104 USA.;Univ Oklahoma, Hlth Sci Ctr, Dept Med, Oklahoma City, OK USA.;US Dept Vet Affairs, Med Ctr, Oklahoma City, OK USA..
    Kovats, Susan
    Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, 825 NE 13th St, Oklahoma City, OK 73104 USA..
    Mariette, Xavier
    Univ Paris Sud, Hop Univ Paris Sud, AP HP, INSERM,U1012, Le Kremlin Bicetre, France..
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Witte, Torsten
    Hannover Med Sch, Clin Immunol & Rheumatol, Hannover, Germany..
    Rischmueller, Maureen
    Queen Elizabeth Hosp, Adelaide, SA, Australia.;Univ Adelaide, Adelaide, SA, Australia..
    Wahren-Herlenius, Marie
    Karolinska Inst, Dept Med, Stockholm, Sweden..
    Omdal, Roald
    Stavanger Univ Hosp, Dept Internal Med, Clin Immunol Unit, Stavanger, Norway..
    Jonsson, Roland
    Univ Bergen, Dept Clin Sci, Broegelmann Res Lab, Bergen, Norway.;Haukeland Hosp, Dept Rheumatol, Bergen, Norway..
    Ng, Wan-Fai
    Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne, Tyne & Wear, England.;Newcastle Univ, NIHR Newcastle Biomed Res Ctr, Newcastle Upon Tyne, Tyne & Wear, England..
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lessard, Christopher J.
    Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, 825 NE 13th St, Oklahoma City, OK 73104 USA.;Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK USA..
    Sivils, Kathy L.
    Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, 825 NE 13th St, Oklahoma City, OK 73104 USA.;Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK USA..
    Identification of a Sjögren's syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 6, article id e1006820Article in journal (Refereed)
    Abstract [en]

    Sjogren's syndrome (SS) is a common, autoimmune exocrinopathy distinguished by keratoconjunctivitis sicca and xerostomia. Patients frequently develop serious complications including lymphoma, pulmonary dysfunction, neuropathy, vasculitis, and debilitating fatigue. Dysregulation of type I interferon (IFN) pathway is a prominent feature of SS and is correlated with increased autoantibody titers and disease severity. To identify genetic determinants of IFN pathway dysregulation in SS, we performed cis-expression quantitative trait locus (eQTL) analyses focusing on differentially expressed type I IFN-inducible transcripts identified through a transcriptome profiling study. Multiple cis-eQTLs were associated with transcript levels of 2'-5'-oligoadenylate synthetase 1 (OAS1) peaking at rs10774671 (PeQTL = 6.05 x 10(-14)). Association of rs10774671 with SS susceptibility was identified and confirmed through meta-analysis of two independent cohorts (P-meta = 2.59 x 10(-9); odds ratio = 0.75; 95% confidence interval = 0.66-0.86). The risk allele of rs10774671 shifts splicing of OAS1 from production of the p46 isoform to multiple alternative transcripts, including p42, p48, and p44. We found that the isoforms were differentially expressed within each genotype in controls and patients with and without autoantibodies. Furthermore, our results showed that the three alternatively spliced isoforms lacked translational response to type I IFN stimulation. The p48 and p44 isoforms also had impaired protein expression governed by the 3' end of the transcripts. The SS risk allele of rs10774671 has been shown by others to be associated with reduced OAS1 enzymatic activity and ability to clear viral infections, as well as reduced responsiveness to IFN treatment. Our results establish OAS1 as a risk locus for SS and support a potential role for defective viral clearance due to altered IFN response as a genetic pathophysiological basis of this complex autoimmune disease.

  • 19.
    Melin, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Rivera, Patricio
    Evidensia Sodra Djursjukhuset, Stockholm, Sweden..
    Arendt, Maja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Univ Cambridge, Dept Vet Med, Cambridge, England..
    Elvers, Ingegerd
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Broad Inst MIT & Harvard, Cambridge, MA USA..
    Murén, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gustafson, Ulla
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden..
    Starkey, Mike
    Anim Hlth Trust, Newmarket, Suffolk, England..
    Borge, Kaja Sverdrup
    Norwegian Univ Life Sci, Dept Basic Sci & Aquat Med, Oslo, Norway..
    Lingaas, Frode
    Norwegian Univ Life Sci, Dept Basic Sci & Aquat Med, Oslo, Norway..
    Haggstrom, Jens
    Swedish Univ Agr Sci, Dept Clin Sci, Uppsala, Sweden..
    Saellstrom, Sara
    Swedish Univ Agr Sci, Dept Clin Sci, Uppsala, Sweden..
    Ronnberg, Henrik
    Swedish Univ Agr Sci, Dept Clin Sci, Uppsala, Sweden..
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Broad Inst MIT & Harvard, Cambridge, MA USA..
    Genome-Wide Analysis Identifies Germ-Line Risk Factors Associated with Canine Mammary Tumours2016In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 12, no 5, article id e1006029Article in journal (Refereed)
    Abstract [en]

    Canine mammary tumours (CMT) are the most common neoplasia in unspayed female dogs. CMTs are suitable naturally occurring models for human breast cancer and share many characteristics, indicating that the genetic causes could also be shared. We have performed a genome-wide association study (GWAS) in English Springer Spaniel dogs and identified a genome-wide significant locus on chromosome 11 (p(raw) = 5.6x10(-7), p(perm) = 0.019). The most associated haplotype spans a 446 kb region overlapping the CDK5RAP2 gene. The CDK5RAP2 protein has a function in cell cycle regulation and could potentially have an impact on response to chemotherapy treatment. Two additional loci, both on chromosome 27, were nominally associated (p(raw) = 1.97x10(-5) and p(raw) = 8.30x10(-6)). The three loci explain 28.1 +/- 10.0% of the phenotypic variation seen in the cohort, whereas the top ten associated regions account for 38.2 +/- 10.8% of the risk. Furthermore, the ten GWAS loci and regions with reduced genetic variability are significantly enriched for snoRNAs and tumour-associated antigen genes, suggesting a role for these genes in CMT development. We have identified several candidate genes associated with canine mammary tumours, including CDK5RAP2. Our findings enable further comparative studies to investigate the genes and pathways in human breast cancer patients.

  • 20. Nica, Alexandra C
    et al.
    Parts, Leopold
    Glass, Daniel
    Nisbet, James
    Barrett, Amy
    Sekowska, Magdalena
    Travers, Mary
    Potter, Simon
    Grundberg, Elin
    Small, Kerrin
    Hedman, Asa K
    Bataille, Veronique
    Tzenova Bell, Jordana
    Surdulescu, Gabriela
    Dimas, Antigone S
    Ingle, Catherine
    Nestle, Frank O
    di Meglio, Paola
    Min, Josine L
    Wilk, Alicja
    Hammond, Christopher J
    Hassanali, Neelam
    Yang, Tsun-Po
    Montgomery, Stephen B
    O'Rahilly, Steve
    Lindgren, Cecilia M
    Zondervan, Krina T
    Soranzo, Nicole
    Barroso, Inês
    Durbin, Richard
    Ahmadi, Kourosh
    Deloukas, Panos
    McCarthy, Mark I
    Dermitzakis, Emmanouil T
    Spector, Timothy D
    The architecture of gene regulatory variation across multiple human tissues: the MuTHER study.2011In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 7, no 2Article in journal (Refereed)
    Abstract [en]

    While there have been studies exploring regulatory variation in one or more tissues, the complexity of tissue-specificity in multiple primary tissues is not yet well understood. We explore in depth the role of cis-regulatory variation in three human tissues: lymphoblastoid cell lines (LCL), skin, and fat. The samples (156 LCL, 160 skin, 166 fat) were derived simultaneously from a subset of well-phenotyped healthy female twins of the MuTHER resource. We discover an abundance of cis-eQTLs in each tissue similar to previous estimates (858 or 4.7% of genes). In addition, we apply factor analysis (FA) to remove effects of latent variables, thus more than doubling the number of our discoveries (1,822 eQTL genes). The unique study design (Matched Co-Twin Analysis--MCTA) permits immediate replication of eQTLs using co-twins (93%-98%) and validation of the considerable gain in eQTL discovery after FA correction. We highlight the challenges of comparing eQTLs between tissues. After verifying previous significance threshold-based estimates of tissue-specificity, we show their limitations given their dependency on statistical power. We propose that continuous estimates of the proportion of tissue-shared signals and direct comparison of the magnitude of effect on the fold change in expression are essential properties that jointly provide a biologically realistic view of tissue-specificity. Under this framework we demonstrate that 30% of eQTLs are shared among the three tissues studied, while another 29% appear exclusively tissue-specific. However, even among the shared eQTLs, a substantial proportion (10%-20%) have significant differences in the magnitude of fold change between genotypic classes across tissues. Our results underline the need to account for the complexity of eQTL tissue-specificity in an effort to assess consequences of such variants for complex traits.

  • 21.
    Nowak, Christoph
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Salihovic, Samira
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ganna, Andrea
    Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA.;Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA.;Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA.;Karolinska Inst, Dept Med Epidemiol & Biostat MEB, Stockholm, Sweden..
    Brandmaier, Stefan
    Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Munich, Germany.;Helmholtz Zentrum Munchen, Inst Epidemiol 2, Munich, Germany..
    Tukiainen, Taru
    Univ Helsinki, FIMM, Helsinki, Finland..
    Broeckling, Corey D.
    Colorado State Univ, Prote & Metabol Facil, Ft Collins, CO 80523 USA..
    Magnusson, Patrik K.
    Karolinska Inst, Dept Med Epidemiol & Biostat MEB, Stockholm, Sweden..
    Prenni, Jessica E.
    Colorado State Univ, Prote & Metabol Facil, Ft Collins, CO 80523 USA..
    Wang-Sattler, Rui
    Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Munich, Germany.;Helmholtz Zentrum Munchen, Inst Epidemiol 2, Munich, Germany.;German Ctr Diabet Res DZD, Munich, Germany..
    Peters, Annette
    Helmholtz Zentrum Munchen, Inst Epidemiol 2, Munich, Germany.;German Ctr Diabet Res DZD, Munich, Germany.;Harvard Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA..
    Strauch, Konstantin
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany.;Univ Munich, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, Munich, Germany..
    Meitinger, Thomas
    Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany.;Tech Univ Munich, Inst Human Genet, Munich, Germany..
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology. Dalarna Univ, Sch Hlth & Social Studies, Falun, Sweden..
    Berne, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Gieger, Christian
    Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Munich, Germany.;Helmholtz Zentrum Munchen, Inst Epidemiol 2, Munich, Germany.;German Ctr Diabet Res DZD, Munich, Germany..
    Ripatti, Samuli
    Univ Helsinki, FIMM, Helsinki, Finland.;Univ Helsinki, Fac Med, Publ Hlth, Helsinki, Finland.;Wellcome Trust Sanger Inst, Hinxton, England..
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Pedersen, Nancy L.
    Karolinska Inst, Dept Med Epidemiol & Biostat MEB, Stockholm, Sweden..
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Stanford Univ, Dept Med, Sch Med, Div Cardiovasc Med, Stanford, CA 94305 USA..
    Fall, Tove
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Effect of Insulin Resistance on Monounsaturated Fatty Acid Levels: A Multi-cohort Non-targeted Metabolomics and Mendelian Randomization Study2016In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 12, no 10, article id e1006379Article in journal (Refereed)
    Abstract [en]

    Insulin resistance (IR) and impaired insulin secretion contribute to type 2 diabetes and cardiovascular disease. Both are associated with changes in the circulating metabolome, but causal directions have been difficult to disentangle. We combined untargeted plasma metabolomics by liquid chromatography/mass spectrometry in three non-diabetic cohorts with Mendelian Randomization (MR) analysis to obtain new insights into early metabolic alterations in IR and impaired insulin secretion. In up to 910 elderly men we found associations of 52 metabolites with hyperinsulinemic-euglycemic clamp-measured IR and/or beta-cell responsiveness (disposition index) during an oral glucose tolerance test. These implicated bile acid, glycerophospholipid and caffeine metabolism for IR and fatty acid biosynthesis for impaired insulin secretion. In MR analysis in two separate cohorts (n = 2,613) followed by replication in three independent studies profiled on different metabolomics platforms (n = 7,824 / 8,961 / 8,330), we discovered and replicated causal effects of IR on lower levels of palmitoleic acid and oleic acid. A trend for a causal effect of IR on higher levels of tyrosine reached significance only in meta-analysis. In one of the largest studies combining "gold standard" measures for insulin responsiveness with non-targeted metabolomics, we found distinct metabolic profiles related to IR or impaired insulin secretion. We speculate that the causal effects on monounsaturated fatty acid levels could explain parts of the raised cardiovascular disease risk in IR that is independent of diabetes development.

  • 22. Parts, Leopold
    et al.
    Hedman, Åsa K
    Wellcome Trust Centre for Human Genetics, University of Oxford.
    Keildson, Sarah
    Knights, Andrew J
    Abreu-Goodger, Cei
    van de Bunt, Martijn
    Guerra-Assunção, José Afonso
    Bartonicek, Nenad
    van Dongen, Stijn
    Mägi, Reedik
    Nisbet, James
    Barrett, Amy
    Rantalainen, Mattias
    Nica, Alexandra C
    Quail, Michael A
    Small, Kerrin S
    Glass, Daniel
    Enright, Anton J
    Winn, John
    Deloukas, Panos
    Dermitzakis, Emmanouil T
    McCarthy, Mark I
    Spector, Timothy D
    Durbin, Richard
    Lindgren, Cecilia M
    Extent, causes, and consequences of small RNA expression variation in human adipose tissue.2012In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 8, no 5Article in journal (Refereed)
    Abstract [en]

    Small RNAs are functional molecules that modulate mRNA transcripts and have been implicated in the aetiology of several common diseases. However, little is known about the extent of their variability within the human population. Here, we characterise the extent, causes, and effects of naturally occurring variation in expression and sequence of small RNAs from adipose tissue in relation to genotype, gene expression, and metabolic traits in the MuTHER reference cohort. We profiled the expression of 15 to 30 base pair RNA molecules in subcutaneous adipose tissue from 131 individuals using high-throughput sequencing, and quantified levels of 591 microRNAs and small nucleolar RNAs. We identified three genetic variants and three RNA editing events. Highly expressed small RNAs are more conserved within mammals than average, as are those with highly variable expression. We identified 14 genetic loci significantly associated with nearby small RNA expression levels, seven of which also regulate an mRNA transcript level in the same region. In addition, these loci are enriched for variants significant in genome-wide association studies for body mass index. Contrary to expectation, we found no evidence for negative correlation between expression level of a microRNA and its target mRNAs. Trunk fat mass, body mass index, and fasting insulin were associated with more than twenty small RNA expression levels each, while fasting glucose had no significant associations. This study highlights the similar genetic complexity and shared genetic control of small RNA and mRNA transcripts, and gives a quantitative picture of small RNA expression variation in the human population.

  • 23. Prokopenko, Inga
    et al.
    Poon, Wenny
    Mägi, Reedik
    Prasad B, Rashmi
    Salehi, S Albert
    Almgren, Peter
    Osmark, Peter
    Bouatia-Naji, Nabila
    Wierup, Nils
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Stančáková, Alena
    Barker, Adam
    Lagou, Vasiliki
    Osmond, Clive
    Xie, Weijia
    Lahti, Jari
    Jackson, Anne U
    Cheng, Yu-Ching
    Liu, Jie
    O'Connell, Jeffrey R
    Blomstedt, Paul A
    Fadista, Joao
    Alkayyali, Sami
    Dayeh, Tasnim
    Ahlqvist, Emma
    Taneera, Jalal
    Lecoeur, Cecile
    Kumar, Ashish
    Hansson, Ola
    Hansson, Karin
    Voight, Benjamin F
    Kang, Hyun Min
    Levy-Marchal, Claire
    Vatin, Vincent
    Palotie, Aarno
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mari, Andrea
    Weedon, Michael N
    Loos, Ruth J F
    Ong, Ken K
    Nilsson, Peter
    Isomaa, Bo
    Tuomi, Tiinamaija
    Wareham, Nicholas J
    Stumvoll, Michael
    Widen, Elisabeth
    Lakka, Timo A
    Langenberg, Claudia
    Tönjes, Anke
    Rauramaa, Rainer
    Kuusisto, Johanna
    Frayling, Timothy M
    Froguel, Philippe
    Walker, Mark
    Eriksson, Johan G
    Ling, Charlotte
    Kovacs, Peter
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.
    McCarthy, Mark I
    Shuldiner, Alan R
    Silver, Kristi D
    Laakso, Markku
    Groop, Leif
    Lyssenko, Valeriya
    A Central Role for GRB10 in Regulation of Islet Function in Man2014In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 4, article id e1004235Article in journal (Refereed)
    Abstract [en]

    Variants in the growth factor receptor-bound protein 10 (GRB10) gene were in a GWAS meta-analysis associated with reduced glucose-stimulated insulin secretion and increased risk of type 2 diabetes (T2D) if inherited from the father, but inexplicably reduced fasting glucose when inherited from the mother. GRB10 is a negative regulator of insulin signaling and imprinted in a parent-of-origin fashion in different tissues. GRB10 knock-down in human pancreatic islets showed reduced insulin and glucagon secretion, which together with changes in insulin sensitivity may explain the paradoxical reduction of glucose despite a decrease in insulin secretion. Together, these findings suggest that tissue-specific methylation and possibly imprinting of GRB10 can influence glucose metabolism and contribute to T2D pathogenesis. The data also emphasize the need in genetic studies to consider whether risk alleles are inherited from the mother or the father.

  • 24.
    Rask-Andersen, Mathias
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Karlsson, Torgny
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Ek, Weronica E
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Johansson, Åsa
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Gene-environment interaction study for BMI reveals interactions between genetic factors and physical activity, alcohol consumption and socioeconomic status.2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 9, article id e1006977Article in journal (Refereed)
    Abstract [en]

    Previous genome-wide association studies (GWAS) have identified hundreds of genetic loci to be associated with body mass index (BMI) and risk of obesity. Genetic effects can differ between individuals depending on lifestyle or environmental factors due to gene-environment interactions. In this study, we examine gene-environment interactions in 362,496 unrelated participants with Caucasian ancestry from the UK Biobank resource. A total of 94 BMI-associated SNPs, selected from a previous GWAS on BMI, were used to construct weighted genetic scores for BMI (GSBMI). Linear regression modeling was used to estimate the effect of gene-environment interactions on BMI for 131 lifestyle factors related to: dietary habits, smoking and alcohol consumption, physical activity, socioeconomic status, mental health, sleeping patterns, as well as female-specific factors such as menopause and childbirth. In total, 15 lifestyle factors were observed to interact with GSBMI, of which alcohol intake frequency, usual walking pace, and Townsend deprivation index, a measure of socioeconomic status, were all highly significant (p = 1.45*10-29, p = 3.83*10-26, p = 4.66*10-11, respectively). Interestingly, the frequency of alcohol consumption, rather than the total weekly amount resulted in a significant interaction. The FTO locus was the strongest single locus interacting with any of the lifestyle factors. However, 13 significant interactions were also observed after omitting the FTO locus from the genetic score. Our analyses indicate that many lifestyle factors modify the genetic effects on BMI with some groups of individuals having more than double the effect of the genetic score. However, the underlying causal mechanisms of gene-environmental interactions are difficult to deduce from cross-sectional data alone and controlled experiments are required to fully characterise the causal factors.

  • 25. Shen, Xia
    et al.
    De Jonge, Jennifer
    Forsberg, Simon K G
    Pettersson, Mats E
    Sheng, Zheya
    Hennig, Lars
    Carlborg, Örjan
    SLU.
    Natural CMT2 variation is associated with genome-wide methylation changes and temperature seasonality.2014In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 12Article in journal (Refereed)
    Abstract [en]

    As Arabidopsis thaliana has colonized a wide range of habitats across the world it is an attractive model for studying the genetic mechanisms underlying environmental adaptation. Here, we used public data from two collections of A. thaliana accessions to associate genetic variability at individual loci with differences in climates at the sampling sites. We use a novel method to screen the genome for plastic alleles that tolerate a broader climate range than the major allele. This approach reduces confounding with population structure and increases power compared to standard genome-wide association methods. Sixteen novel loci were found, including an association between Chromomethylase 2 (CMT2) and temperature seasonality where the genome-wide CHH methylation was different for the group of accessions carrying the plastic allele. Cmt2 mutants were shown to be more tolerant to heat-stress, suggesting genetic regulation of epigenetic modifications as a likely mechanism underlying natural adaptation to variable temperatures, potentially through differential allelic plasticity to temperature-stress.

  • 26.
    Shungin, Dmitry
    et al.
    Lund Univ, Diabet Ctr, Skane Univ Hosp, Dept Clin Sci,Genet & Mol Epidemiol Unit, Malmo, Sweden.;Umea Univ, Dept Odontol, Umea, Sweden.;Umea Univ, Dept Publ Hlth & Clin Med, Unit Med, Umea, Sweden.;MIT, Broad Inst, 77 Massachusetts Ave, Cambridge, MA 02139 USA.;Harvard Univ, Cambridge, MA 02138 USA..
    Deng, Wei Q.
    Univ Toronto, Dept Stat Sci, Toronto, ON, Canada..
    Varga, Tibor V.
    Lund Univ, Diabet Ctr, Skane Univ Hosp, Dept Clin Sci,Genet & Mol Epidemiol Unit, Malmo, Sweden.;Univ Copenhagen, Fac Hlth & Med Sci, Translat Dis Syst Biol Grp, Novo Nordisk Fdn Ctr Prot Res, Copenhagen, Denmark.;Lund Univ, Exercise Physiol Grp, Dept Hlth Sci, Lund, Sweden..
    Luan, Jian'an
    Univ Cambridge, Inst Metab Sci, Addenbrookes Hosp, MRC Epidemiol Unit, Cambridge, England..
    Mihailov, Evelin
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia..
    Metspalu, Andres
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia.;Univ Tartu, Inst Mol & Cell Biol, Tartu, Estonia..
    Morris, Andrew P.
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia.;Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Liverpool, Dept Biostat, Liverpool, Merseyside, England..
    Forouhi, Nita G.
    Univ Cambridge, Inst Metab Sci, Addenbrookes Hosp, MRC Epidemiol Unit, Cambridge, England..
    Lindgren, Cecilia
    MIT, Broad Inst, 77 Massachusetts Ave, Cambridge, MA 02139 USA.;Harvard Univ, Cambridge, MA 02138 USA.;Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Magnusson, Patrik K. E.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Pedersen, Nancy L.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Hallmans, Göran
    Umea Univ, Dept Biobank Res, Umea, Sweden..
    Chu, Audrey Y.
    Harvard Med Sch, Boston, MA USA..
    Justice, Anne E.
    Univ North Carolina Chapel Hill, Dept Epidemiol, Chapel Hill, NC USA..
    Graff, Mariaelisa
    Univ North Carolina Chapel Hill, Dept Epidemiol, Chapel Hill, NC USA..
    Winkler, Thomas W.
    Univ Regensburg, Dept Genet Epidemiol, Regensburg, DE, Germany..
    Rose, Lynda M.
    Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA..
    Langenberg, Claudia
    Univ Cambridge, Inst Metab Sci, Addenbrookes Hosp, MRC Epidemiol Unit, Cambridge, England.;UCL, Dept Epidemiol & Publ Hlth, London, England..
    Cupples, L. Adrienne
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA.;NHLBI Framingham Heart Study, Framingham, MA USA..
    Ridker, Paul M.
    Harvard Med Sch, Boston, MA USA.;Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA..
    Wareham, Nicholas J.
    Univ Cambridge, Inst Metab Sci, Addenbrookes Hosp, MRC Epidemiol Unit, Cambridge, England..
    Ong, Ken K.
    Univ Cambridge, Inst Metab Sci, Addenbrookes Hosp, MRC Epidemiol Unit, Cambridge, England..
    Loos, Ruth J. F.
    Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY USA.;Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY USA.;Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY USA..
    Chasman, Daniel I.
    Harvard Med Sch, Boston, MA USA.;Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA..
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA..
    Kilpeläinen, Tuomas O.
    Univ Copenhagen, Fac Hlth & Med Sci, Sect Metab Genet, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark..
    Scott, Robert A.
    Univ Cambridge, Inst Metab Sci, Addenbrookes Hosp, MRC Epidemiol Unit, Cambridge, England..
    Magi, Reedik
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia.;Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Pare, Guillaume
    McMaster Univ, Dept Pathol & Mol Med, Hamilton, ON, Canada..
    Franks, Paul W.
    Lund Univ, Diabet Ctr, Skane Univ Hosp, Dept Clin Sci,Genet & Mol Epidemiol Unit, Malmo, Sweden.;Umea Univ, Dept Publ Hlth & Clin Med, Unit Med, Umea, Sweden.;Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA.;Univ Oxford, Radcliff Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Ranking and characterization of established BMI and lipid associated loci as candidates for gene-environment interactions2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 6, article id e1006812Article in journal (Refereed)
    Abstract [en]

    Phenotypic variance heterogeneity across genotypes at a single nucleotide polymorphism (SNP) may reflect underlying gene-environment (GxE) or gene-gene interactions. We modeled variance heterogeneity for blood lipids and BMI in up to 44,211 participants and investigated relationships between variance effects (P-v), GxE interaction effects (with smoking and physical activity), and marginal genetic effects (P-m). Correlations between P-v and P-m were stronger for SNPs with established marginal effects (Spearman's rho = 0.401 for triglycerides, and rho = 0.236 for BMI) compared to all SNPs. When P-v and P-m were compared for all pruned SNPs, only BMI was statistically significant (Spearman's rho = 0.010). Overall, SNPs with established marginal effects were overrepresented in the nominally significant part of the P-v distribution (P-binomial < 0.05). SNPs from the top 1% of the P-m distribution for BMI had more significant P-v values (Pmann-Whitney = 1.46x10(-5)), and the odds ratio of SNPs with nominally significant (< 0.05) P-m and P-v was 1.33 (95% CI: 1.12, 1.57) for BMI. Moreover, BMI SNPs with nominally significant GxE interaction P-values (Pint < 0.05) were enriched with nominally significant P-v values (P-binomial = 8.63x10(-9) and 8.52x10(-7) for SNP x smoking and SNP x physical activity, respectively). We conclude that some loci with strong marginal effects may be good candidates for GxE, and variance-based prioritization can be used to identify them.

  • 27.
    Smeds, Linnéa
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Mugal, Carina F
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Qvarnström, Anna
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Ellegren, Hans
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    High-Resolution Mapping of Crossover and Non-crossover Recombination Events by Whole-Genome Re-sequencing of an Avian Pedigree2016In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 12, no 5, article id e1006044Article in journal (Refereed)
    Abstract [en]

    Recombination is an engine of genetic diversity and therefore constitutes a key process in evolutionary biology and genetics. While the outcome of crossover recombination can readily be detected as shuffled alleles by following the inheritance of markers in pedigreed families, the more precise location of both crossover and non-crossover recombination events has been difficult to pinpoint. As a consequence, we lack a detailed portrait of the recombination landscape for most organisms and knowledge on how this landscape impacts on sequence evolution at a local scale. To localize recombination events with high resolution in an avian system, we performed whole-genome re-sequencing at high coverage of a complete three-generation collared flycatcher pedigree. We identified 325 crossovers at a median resolution of 1.4 kb, with 86% of the events localized to <10 kb intervals. Observed crossover rates were in excellent agreement with data from linkage mapping, were 52% higher in male (3.56 cM/Mb) than in female meiosis (2.28 cM/Mb), and increased towards chromosome ends in male but not female meiosis. Crossover events were non-randomly distributed in the genome with several distinct hot-spots and a concentration to genic regions, with the highest density in promoters and CpG islands. We further identified 267 non-crossovers, whose location was significantly associated with crossover locations. We detected a significant transmission bias (0.18) in favour of 'strong' (G, C) over 'weak' (A, T) alleles at non-crossover events, providing direct evidence for the process of GC-biased gene conversion in an avian system. The approach taken in this study should be applicable to any species and would thereby help to provide a more comprehensive portray of the recombination landscape across organism groups.

  • 28.
    Thalmann, Doreen Schwochow
    et al.
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden.;Univ Paris Saclay, GABI, INRA, AgroParisTech, F-78350 Jouy En Josas, France..
    Ring, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Sundström, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cao, Xiaofang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Larsson, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kerje, Susanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Höglund, Andrey
    Linkoping Univ, AVIAN Behav Genom & Physiol Grp, IFM Biol, Linkoping, Sweden..
    Fogelholm, Jesper
    Linkoping Univ, AVIAN Behav Genom & Physiol Grp, IFM Biol, Linkoping, Sweden..
    Wright, Dominic
    Linkoping Univ, AVIAN Behav Genom & Physiol Grp, IFM Biol, Linkoping, Sweden..
    Jemth, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Bed'Hom, Bertrand
    Univ Paris Saclay, GABI, INRA, AgroParisTech, F-78350 Jouy En Josas, France..
    Dorshorst, Ben
    Virginia Tech, Dept Anim & Poultry Sci, Blacksburg, VA USA..
    Tixier-Boichard, Michele
    Univ Paris Saclay, GABI, INRA, AgroParisTech, F-78350 Jouy En Josas, France..
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden.;Texas A&M Univ, Coll Vet Med & Biomed Sci, Dept Vet Integrat Biosci, College Stn, TX 77843 USA..
    The evolution of Sex-linked barring alleles in chickens involves both regulatory and coding changes in CDKN2A2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 4, article id e1006665Article in journal (Refereed)
    Abstract [en]

    Sex-linked barring is a fascinating plumage pattern in chickens recently shown to be associated with two non-coding and two missense mutations affecting the ARF transcript at the CDKN2A tumor suppressor locus. It however remained a mystery whether all four mutations are indeed causative and how they contribute to the barring phenotype. Here, we show that Sex-linked barring is genetically heterogeneous, and that the mutations form three functionally different variant alleles. The B0 allele carries only the two non-coding changes and is associated with the most dilute barring pattern, whereas the B1 and B2 alleles carry both the two non-coding changes and one each of the two missense mutations causing the Sex-linked barring and Sex-linked dilution phenotypes, respectively. The data are consistent with evolution of alleles where the non-coding changes occurred first followed by the two missense mutations that resulted in a phenotype more appealing to humans. We show that one or both of the non-coding changes are cis-regulatory mutations causing a higher CDKN2A expression, whereas the missense mutations reduce the ability of ARF to interact with MDM2. Caspase assays for all genotypes revealed no apoptotic events and our results are consistent with a recent study indicating that the loss of melanocyte progenitors in Sex-linked barring in chicken is caused by premature differentiation and not apoptosis. Our results show that CDKN2A is a major locus driving the differentiation of avian melanocytes in a temporal and spatial manner.

  • 29.
    Truve, Katarina
    et al.
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Bioinformat Core Facil, Gothenburg, Sweden..
    Dickinson, Peter
    Univ Calif Davis, Sch Vet Med, Dept Surg & Radiol Sci, Davis, CA 95616 USA..
    Xiong, Anqi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    York, Daniel
    Univ Calif Davis, Sch Vet Med, Dept Surg & Radiol Sci, Davis, CA 95616 USA..
    Jayashankar, Kartika
    Univ Calif Davis, Sch Vet Med, Dept Populat Hlth & Reprod, Davis, CA 95616 USA..
    Pielberg, Gerli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Koltookian, Michele
    Broad Inst Harvard & Massachusetts Inst Technol M, Cambridge, MA USA..
    Murén, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Fuxelius, Hans-Henrik
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden..
    Weishaupt, Holger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Swartling, Fredrik J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Andersson, Göran
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden..
    Hedhammar, Ake
    Swedish Univ Agr Sci, Dept Clin Sci, Uppsala, Sweden..
    Bongcam-Rudloff, Erik
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden..
    Forsberg-Nilsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Bannasch, Danika
    Univ Calif Davis, Sch Vet Med, Dept Populat Hlth & Reprod, Davis, CA 95616 USA..
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Broad Inst Harvard & Massachusetts Inst Technol M, Cambridge, MA USA..
    Utilizing the Dog Genome in the Search for Novel Candidate Genes Involved in Glioma Development-Genome Wide Association Mapping followed by Targeted Massive Parallel Sequencing Identifies a Strongly Associated Locus2016In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 12, no 5, article id e1006000Article in journal (Refereed)
    Abstract [en]

    Gliomas are the most common form of malignant primary brain tumors in humans and second most common in dogs, occurring with similar frequencies in both species. Dogs are valuable spontaneous models of human complex diseases including cancers and may provide insight into disease susceptibility and oncogenesis. Several brachycephalic breeds such as Boxer, Bulldog and Boston Terrier have an elevated risk of developing glioma, but others, including Pug and Pekingese, are not at higher risk. To identify glioma-associated genetic susceptibility factors, an across-breed genome-wide association study (GWAS) was performed on 39 dog glioma cases and 141 controls from 25 dog breeds, identifying a genome-wide significant locus on canine chromosome (CFA) 26 (p = 2.8 x 10(-8)). Targeted re-sequencing of the 3.4 Mb candidate region was performed, followed by genotyping of the 56 SNVs that best fit the association pattern between the re-sequenced cases and controls. We identified three candidate genes that were highly associated with glioma susceptibility: CAMKK2, P2RX7 and DENR. CAMKK2 showed reduced expression in both canine and human brain tumors, and a non-synonymous variant in P2RX7, previously demonstrated to have a 50% decrease in receptor function, was also associated with disease. Thus, one or more of these genes appear to affect glioma susceptibility.

  • 30.
    von Salome, Jenny
    et al.
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden..
    Boonstra, Philip S.
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA..
    Karimi, Masoud
    Karolinska Univ Hosp, Radiumhemmet, Dept Oncol, Stockholm, Sweden..
    Silander, Gustav
    Umea Univ, Dept Radiat Sci, Umea, Sweden..
    Stenmark-Askmalm, Marie
    Linkoping Univ, Dept Oncol, Linkoping, Sweden.;Off Med Serv, Div Lab Med, Dept Clin Genet, Lund, Sweden..
    Gebre-Medhin, Samuel
    Off Med Serv, Div Lab Med, Dept Clin Genet, Lund, Sweden.;Lund Univ, Div Clin Genet, Dept Lab Med, Lund, Sweden..
    Aravidis, Christos
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Nilbert, Mef
    Lund Univ, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden.;Univ Copenhagen, Hvidovre Hosp, Clin Res Ctr, Hvidovre, Denmark..
    Lindblom, Annika
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden..
    Lagerstedt-Robinson, Kristina
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden..
    Genetic anticipation in Swedish Lynch syndrome families2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 10, article id e1007012Article in journal (Refereed)
    Abstract [en]

    Among hereditary colorectal cancer predisposing syndromes, Lynch syndrome (LS) caused by mutations in DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2 is the most common. Patients with LS have an increased risk of early onset colon and endometrial cancer, but also other tumors that generally have an earlier onset compared to the general population. However, age at first primary cancer varies within families and genetic anticipation, i.e. decreasing age at onset in successive generations, has been suggested in LS. Anticipation is a well-known phenomenon in e.g neurodegenerative diseases and several reports have studied anticipation in heritable cancer. The purpose of this study is to determine whether anticipation can be shown in a large cohort of Swedish LS families referred to the regional departments of clinical genetics in Lund, Stockholm, Linkoping, Uppsala and Umea between the years 1990-2013. We analyzed a homogenous group of mutation carriers, utilizing information from both affected and non-affected family members. In total, 239 families with a mismatch repair gene mutation (96 MLH1 families, 90 MSH2 families including one family with an EPCAM-MSH2 deletion, 39 MSH6 families, 12 PMS2 families, and 2 MLH1+PMS2 families) comprising 1028 at-risk carriers were identified among the Swedish LS families, of which 1003 mutation carriers had available follow-up information and could be included in the study. Using a normal random effects model (NREM) we estimate a 2.1 year decrease in age of diagnosis per generation. An alternative analysis using a mixed-effects Cox proportional hazards model (COX-R) estimates a hazard ratio of exp(0.171), or about 1.19, for age of diagnosis between consecutive generations. LS-associated gene-specific anticipation effects are evident for MSH2 (2.6 years/generation for NREM and hazard ratio of 1.33 for COX-R) and PMS2 (7.3 years/generation and hazard ratio of 1.86). The estimated anticipation effects for MLH1 and MSH6 are smaller.

  • 31.
    Wallberg, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pirk, Christian W.
    Univ Pretoria, Dept Zool & Entomol, Pretoria, South Africa..
    Allsopp, Mike H.
    Agr Res Council, Plant Protect Res Inst, Stellenbosch, South Africa..
    Webster, Matthew T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Identification of Multiple Loci Associated with Social Parasitism in Honeybees2016In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 12, no 6, article id e1006097Article in journal (Refereed)
    Abstract [en]

    In colonies of the honeybee Apis mellifera, the queen is usually the only reproductive female, which produces new females (queens and workers) by laying fertilized eggs. However, in one subspecies of A. mellifera, known as the Cape bee (A. m. capensis), worker bees reproduce asexually by thelytoky, an abnormal form of meiosis where two daughter nucleii fuse to form single diploid eggs, which develop into females without being fertilized. The Cape bee also exhibits a suite of phenotypes that facilitate social parasitism whereby workers lay such eggs in foreign colonies so their offspring can exploit their resources. The genetic basis of this switch to social parasitism in the Cape bee is unknown. To address this, we compared genome variation in a sample of Cape bees with other African populations. We find genetic divergence between these populations to be very low on average but identify several regions of the genome with extreme differentiation. The regions are strongly enriched for signals of selection in Cape bees, indicating that increased levels of positive selection have produced the unique set of derived phenotypic traits in this subspecies. Genetic variation within these regions allows unambiguous genetic identification of Cape bees and likely underlies the genetic basis of social parasitism. The candidate loci include genes involved in ecdysteroid signaling and juvenile hormone and dopamine biosynthesis, which may regulate worker ovary activation and others whose products localize at the centrosome and are implicated in chromosomal segregation during meiosis. Functional analysis of these loci will yield insights into the processes of reproduction and chemical signaling in both parasitic and non-parasitic populations and advance understanding of the process of normal and atypical meiosis.

  • 32.
    Wallberg, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Schoening, Caspar
    Inst Bee Res, Hohen Neuendorf, Germany..
    Webster, Matthew Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hasselmann, Martin
    Univ Hohenheim, Stuttgart, Germany..
    Two extended haplotype blocks are associated with adaptation to high altitude habitats in East African honey bees2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 5, article id e1006792Article in journal (Refereed)
    Abstract [en]

    Understanding the genetic basis of adaption is a central task in biology. Populations of the honey bee Apis mellifera that inhabit the mountain forests of East Africa differ in behavior and morphology from those inhabiting the surrounding lowland savannahs, which likely reflects adaptation to these habitats. We performed whole genome sequencing on 39 samples of highland and lowland bees from two pairs of populations to determine their evolutionary affinities and identify the genetic basis of these putative adaptations. We find that in general, levels of genetic differentiation between highland and lowland populations are very low, consistent with them being a single panmictic population. However, we identify two loci on chromosomes 7 and 9, each several hundred kilobases in length, which exhibit near fixation for different haplotypes between highland and lowland populations. The highland haplotypes at these loci are extremely rare in samples from the rest of the world. Patterns of segregation of genetic variants suggest that recombination between haplotypes at each locus is suppressed, indicating that they comprise independent structural variants. The haplotype on chromosome 7 harbors nearly all octopamine receptor genes in the honey bee genome. These have a role in learning and foraging behavior in honey bees and are strong candidates for adaptation to highland habitats. Molecular analysis of a putative breakpoint indicates that it may disrupt the coding sequence of one of these genes. Divergence between the highland and lowland haplotypes at both loci is extremely high suggesting that they are ancient balanced polymorphisms that greatly predate divergence between the extant honey bee subspecies.

  • 33.
    Williams, Michael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Goergen, Philip
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Rajendran, Jayasimman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Zheleznyakova, Galina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Hägglund, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Perland, Emelie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Bagchi, Sonchita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Kalogeropoulou, Argyro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Khan, Zaid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Obesity-linked homologues TfAP-2 and Twz establish meal frequency in Drosophila melanogaster2014In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 9, p. e1004499-Article in journal (Refereed)
    Abstract [en]

    In all animals managing the size of individual meals and frequency of feeding is crucial for metabolic homeostasis. In the current study we demonstrate that the noradrenalin analogue octopamine and the cholecystokinin (CCK) homologue Drosulfakinin (Dsk) function downstream of TfAP-2 and Tiwaz (Twz) to control the number of meals in adult flies. Loss of TfAP-2 or Twz in octopaminergic neurons increased the size of individual meals, while overexpression of TfAP-2 significantly decreased meal size and increased feeding frequency. Of note, our study reveals that TfAP-2 and Twz regulate octopamine signaling to initiate feeding; then octopamine, in a negative feedback loop, induces expression of Dsk to inhibit consummatory behavior. Intriguingly, we found that the mouse TfAP-2 and Twz homologues, AP-2β and Kctd15, co-localize in areas of the brain known to regulate feeding behavior and reward, and a proximity ligation assay (PLA) demonstrated that AP-2β and Kctd15 interact directly in a mouse hypothalamus-derived cell line. Finally, we show that in this mouse hypothalamic cell line AP-2β and Kctd15 directly interact with Ube2i, a mouse sumoylation enzyme, and that AP-2β may itself be sumoylated. Our study reveals how two obesity-linked homologues regulate metabolic homeostasis by modulating consummatory behavior.

  • 34.
    Winkler, Thomas W.
    et al.
    Univ Regensburg, Inst Epidemiol & Prevent Med, Dept Genet Epidemiol, D-93053 Regensburg, Germany..
    Justice, Anne E.
    Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA..
    Graff, Mariaelisa
    Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA..
    Barata, Llilda
    Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63110 USA..
    Feitosa, Mary F.
    Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63110 USA..
    Chu, Su
    Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Czajkowski, Jacek
    Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63110 USA..
    Esko, Tonu
    MIT, Broad Inst, Cambridge, MA 02139 USA.;Harvard Univ, Cambridge, MA 02138 USA.;Boston Childrens Hosp, Div Endocrinol, Boston, MA USA.;Boston Childrens Hosp, Div Genet, Boston, MA USA.;Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA USA.;Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA..
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Kilpelainen, Tuomas O.
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Genet, Copenhagen, Denmark.;Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England..
    Lu, Yingchang
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Dept Prevent Med, New York, NY 10029 USA..
    Magi, Reedik
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia.;Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Mihailov, Evelin
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia..
    Pers, Tune H.
    Boston Childrens Hosp, Div Endocrinol, Boston, MA USA.;Boston Childrens Hosp, Div Genet, Boston, MA USA.;Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.;Broad Inst MIT & Harvard, Med & Populat Genet Program, Cambridge, MA USA..
    Rueeger, Sina
    Swiss Inst Bioinformat, Lausanne, Switzerland.;Univ Hosp Lausanne CHUV, Inst Social & Prevent Med, Lausanne, Switzerland..
    Teumer, Alexander
    Univ Med Greifswald, Inst Community Med, Greifswald, Germany.;Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany..
    Ehret, Georg B.
    Univ Hosp Geneva, Dept Specialties Internal Med, Geneva, Switzerland.;Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Ctr Complex Dis Genom, Baltimore, MD USA..
    Ferreira, Teresa
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Heard-Costa, Nancy L.
    Boston Univ, Sch Med, Dept Neurol, Boston, MA 02215 USA.;NHLBI, Framingham Heart Study, Framingham, MA USA..
    Karjalainen, Juha
    Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands..
    Lagou, Vasiliki
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Mahajan, Anubha
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Neinast, Michael D.
    Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA..
    Prokopenko, Inga
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Hammersmith Hosp, London, England.;Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Genom Common Dis, London, England..
    Simino, Jeannette
    Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA..
    Teslovich, Tanya M.
    Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Jansen, Rick
    Vrije Univ Amsterdam Med Ctr, Dept Psychiat, Amsterdam, Netherlands.;Vrije Univ Amsterdam Med Ctr, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands..
    Westra, Harm-Jan
    Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA.;Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA.;Brigham & Womens Hosp, Dept Med, Div Rheumatol, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Boston, MA 02115 USA.;Partners Ctr Personalized Genet Med, Boston, MA USA..
    White, Charles C.
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA..
    Absher, Devin
    HudsonAlpha Inst Biotechnol, Huntsville, AL USA..
    Ahluwalia, Tarunveer S.
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Genet, Copenhagen, Denmark.;Steno Diabet Ctr A S, Gentofte, Denmark.;Univ Copenhagen, Herlev & Gentofte Hosp, COPSAC, Copenhagen, Denmark..
    Ahmad, Shafqat
    Skane Univ Hosp Malmo, Dept Clin Sci, Genet & Mol Epidemiol Unit, Malmo, Sweden..
    Albrecht, Eva
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany..
    Alves, Alexessander Couto
    Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, MRC Hlth Protect Agcy HPA Ctr Environm & Hlth, Dept Epidemiol & Biostat, London, England..
    Bragg-Gresham, Jennifer L.
    Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    de Craen, Anton J. M.
    Leiden Univ Med Ctr, Dept Gerontol & Geriatr, Leiden, Netherlands..
    Bis, Joshua C.
    Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA.;Univ Washington, Dept Med, Seattle, WA 98195 USA..
    Bonnefond, Amelie
    CNRS, UMR 8199, Lille, France.;European Genom Inst Diabet, Lille, France.;Univ Lille 2, Lille, France..
    Boucher, Gabrielle
    Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada..
    Cadby, Gemma
    Univ Western Australia, Ctr Genet Origins Hlth & Dis, Crawley, WA, Australia..
    Cheng, Yu-Ching
    VA Maryland Hlth Care Syst, Baltimore, MD USA.;Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA..
    Chiang, Charleston W. K.
    Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA USA..
    Delgado, Graciela
    Heidelberg Univ, Mannheim Med Fac, Dept Med 5, Mannheim, Germany..
    Demirkan, Ayse
    Erasmus MC, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands..
    Dueker, Nicole
    Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA..
    Eklund, Niina
    Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland.;Natl Inst Hlth & Welf, Publ Hlth Genom Unit, Helsinki, Finland.;Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland..
    Eiriksdottir, Gudny
    Iceland Heart Assoc, Kopavogur, Iceland..
    Eriksson, Joel
    Univ Gothenburg, Sahlgrenska Acad, Ctr Bone & Arthrit Res, Inst Med,Dept Internal Med & Clin Nutr, Gothenburg, Sweden..
    Feenstra, Bjarke
    Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark..
    Fischer, Krista
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia..
    Frau, Francesca
    Univ Milan, Dept Hlth Sci, Milan, Italy.;Filarete Fdn, Genom & Bioinformat Unit, Milan, Italy..
    Galesloot, Tessel E.
    Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Dept Hlth Evidence, NL-6525 ED Nijmegen, Netherlands..
    Geller, Frank
    Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark..
    Goel, Anuj
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Div Cardiovac Med, Oxford, England..
    Gorski, Mathias
    Univ Regensburg, Inst Epidemiol & Prevent Med, Dept Genet Epidemiol, D-93053 Regensburg, Germany.;Univ Hosp Regensburg, Dept Nephrol, Regensburg, Germany..
    Grammer, Tanja B.
    Heidelberg Univ, Mannheim Med Fac, Dept Med 5, Mannheim, Germany..
    Gustafsson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Haitjema, Saskia
    UMCU, Expt Cardiol & Lab Clin Chem, Utrecht, Netherlands..
    Hottenga, Jouke-Jan
    Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands..
    Huffman, Jennifer E.
    NHLBI, Framingham Heart Study, Framingham, MA USA.;Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland..
    Jackson, Anne U.
    Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Jacobs, Kevin B.
    NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA.;NCI, Core Genotyping Facil, SAIC Frederick Inc, Frederick, MD 21701 USA..
    Johansson, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Kaakinen, Marika
    Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, MRC Hlth Protect Agcy HPA Ctr Environm & Hlth, Dept Epidemiol & Biostat, London, England.;Univ Oulu, Inst Hlth Sci, Oulu, Finland..
    Kleber, Marcus E.
    Heidelberg Univ, Mannheim Med Fac, Dept Med 5, Mannheim, Germany..
    Lahti, Jari
    Folkhalsan Res Ctr, Helsinki, Finland.;Univ Helsinki, Inst Behav Sci, Helsinki, Finland..
    Leach, Irene Mateo
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands..
    Lehne, Benjamin
    Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London, England..
    Liu, Youfang
    Univ N Carolina Chapel Hill, Thurston Arthrit Res Ctr, Chaper Hill, NC USA..
    Lo, Ken Sin
    Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada..
    Lorentzon, Mattias
    Univ Gothenburg, Sahlgrenska Acad, Ctr Bone & Arthrit Res, Inst Med,Dept Internal Med & Clin Nutr, Gothenburg, Sweden..
    Luan, Jian'an
    Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England..
    Madden, Pamela A. F.
    Washington Univ, Sch Med, St Louis, MO USA..
    Mangino, Massimo
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England..
    McKnight, Barbara
    Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA.;Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Program Biostat & Biomath, Seattle, WA 98104 USA.;Univ Washington, Dept Biostat, Seattle, WA 98195 USA..
    Medina-Gomez, Carolina
    NCHA, NGI, Leiden, Netherlands.;Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.;Erasmus MC, Dept Internal Med, Rotterdam, Netherlands..
    Monda, Keri L.
    Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA.;Amgen Inc, Ctr Observat Res, Thousand Oaks, CA 91320 USA..
    Montasser, May E.
    Univ Maryland, Sch Med, Dept Med, Div Endocrinol Diabet & Nutr,Program Personalized, Baltimore, MD 21201 USA..
    Mueller, Gabriele
    Univ Dresden, Med Fac Carl Gustav Carus, Ctr Evidence Based Healthcare, Dresden, Germany..
    Mueller-Nurasyid, Martina
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany.;Univ Munich, Univ Hosp Grosshadern, Dept Med 1, D-81377 Munich, Germany.;Univ Munich, Inst Med Informat Biometry & Epidemiol, Chair Genet Epidemiol, D-81377 Munich, Germany.;Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Munich, Germany..
    Nolte, Ilja M.
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands..
    Panoutsopoulou, Kalliope
    Wellcome Trust Sanger Inst, Human Genet, Cambridge, England..
    Pascoe, Laura
    Newcastle Univ, Inst Cell & Mol Biosci, Newcastle, NSW, Australia..
    Paternoster, Lavinia
    Univ Bristol, Sch Social & Community Med, MRC Integrat Epidemiol Unit, Bristol, Avon, England..
    Rayner, Nigel W.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Wellcome Trust Sanger Inst, Human Genet, Cambridge, England..
    Renstrom, Frida
    Skane Univ Hosp Malmo, Dept Clin Sci, Genet & Mol Epidemiol Unit, Malmo, Sweden..
    Rizzi, Federica
    Univ Milan, Dept Hlth Sci, Milan, Italy.;Filarete Fdn, Genom & Bioinformat Unit, Milan, Italy..
    Rose, Lynda M.
    Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA..
    Ryan, Kathy A.
    Univ Maryland, Sch Med, Dept Med, Div Endocrinol Diabet & Nutr,Program Personalized, Baltimore, MD 21201 USA..
    Salo, Perttu
    Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland.;Natl Inst Hlth & Welf, Publ Hlth Genom Unit, Helsinki, Finland..
    Sanna, Serena
    CNR, Ist Ric Genet & Biomed, Monserrato, Italy..
    Scharnagl, Hubert
    Med Univ Graz, Inst Clin Med, Graz, Austria.;Med Univ Graz, Chem Lab Diagnost, Graz, Austria..
    Shi, Jianxin
    NCI, Bethesda, MD 20892 USA..
    Smith, Albert Vernon
    Iceland Heart Assoc, Kopavogur, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    Southam, Lorraine
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Wellcome Trust Sanger Inst, Human Genet, Cambridge, England..
    Stancakova, Alena
    Univ Eastern Finland, Dept Med, Kuopio, Finland.;Kuopio Univ Hosp, SF-70210 Kuopio, Finland..
    Steinthorsdottir, Valgerdur
    Amgen Inc, deCODE Genet, Reykjavik, Iceland..
    Strawbridge, Rona J.
    Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Stockholm, Sweden.;Karolinska Univ Hosp, Ctr Mol Med, Stockholm, Sweden..
    Sung, Yun Ju
    Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA..
    Tachmazidou, Ioanna
    Wellcome Trust Sanger Inst, Human Genet, Cambridge, England..
    Tanaka, Toshiko
    NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA..
    Thorleifsson, Gudmar
    Amgen Inc, deCODE Genet, Reykjavik, Iceland..
    Trompet, Stella
    Leiden Univ Med Ctr, Dept Gerontol & Geriatr, Leiden, Netherlands.;Leiden Univ Med Ctr, Dept Cardiol, Leiden, Netherlands..
    Pervjakova, Natalia
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia.;Natl Inst Hlth & Welf, Publ Hlth Genom Unit, Helsinki, Finland.;Univ Tartu, Inst Cell & Mol Biol, Dept Biotechnol, EE-50090 Tartu, Estonia.;Univ Helsinki, Helsinki, Finland..
    Tyrer, Jonathan P.
    Univ Cambridge, Dept Oncol, Cambridge, England..
    Vandenput, Liesbeth
    Univ Gothenburg, Sahlgrenska Acad, Ctr Bone & Arthrit Res, Inst Med,Dept Internal Med & Clin Nutr, Gothenburg, Sweden..
    van der Laan, Sander W.
    UMCU, Expt Cardiol & Lab Clin Chem, Utrecht, Netherlands..
    van der Velde, Nathalie
    Erasmus MC, Dept Internal Med, Rotterdam, Netherlands.;Univ Amsterdam, Acad Med Ctr, Dept Internal Med, Geriatr Med Sect, NL-1105 AZ Amsterdam, Netherlands..
    van Setten, Jessica
    Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands..
    van Vliet-Ostaptchouk, Jana V.
    Univ Groningen, Univ Med Ctr Groningen, Dept Endocrinol, Groningen, Netherlands..
    Verweij, Niek
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands..
    Vlachopoulou, Efthymia
    Univ Helsinki, Transplantat Lab, Haartman Inst, Helsinki, Finland..
    Waite, Lindsay L.
    HudsonAlpha Inst Biotechnol, Huntsville, AL USA..
    Wang, Sophie R.
    Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.;Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA.;Boston Childrens Hosp, Div Endocrinol, Boston, MA USA.;Boston Childrens Hosp, Div Genet, Boston, MA USA.;Boston Childrens Hosp, Div Endocrinol, Boston, MA USA.;Boston Childrens Hosp, Program Genom, Boston, MA USA..
    Wang, Zhaoming
    NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA.;NCI, Core Genotyping Facil, SAIC Frederick Inc, Frederick, MD 21701 USA..
    Wild, Sarah H.
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland..
    Willenborg, Christina
    Hamburg Kiel Lubeck, DZHK German Ctr Cardiovasc Res, Lubeck, Germany.;Univ Lubeck, Inst Integrat & Expt Genom, Lubeck, Germany..
    Wilson, James F.
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Ctr Global Hlth Res, Edinburgh, Midlothian, Scotland..
    Wong, Andrew
    MRC Unit Lifelong Hlth & Ageing UCL, London, England..
    Yang, Jian
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia..
    Yengo, Loic
    CNRS, UMR 8199, Lille, France.;European Genom Inst Diabet, Lille, France.;Univ Lille 2, Lille, France..
    Yerges-Armstrong, Laura M.
    Univ Maryland, Sch Med, Dept Med, Div Endocrinol Diabet & Nutr,Program Personalized, Baltimore, MD 21201 USA..
    Yu, Lei
    Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA..
    Zhang, Weihua
    Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London, England.;Ealing Hosp NHS Trust, Southall, Middx, England..
    Zhao, Jing Hua
    Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England..
    Andersson, Ehm A.
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Genet, Copenhagen, Denmark..
    Bakker, Stephan J. L.
    Univ Groningen, Univ Med Ctr Groningen, Dept Med, Groningen, Netherlands..
    Baldassarre, Damiano
    IRCCS, Ctr Cardiol Monzino, Milan, Italy.;Univ Milan, Dipartimento Sci Farmacol & Biomol, Milan, Italy..
    Banasik, Karina
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Genet, Copenhagen, Denmark..
    Barcella, Matteo
    Univ Milan, Dept Hlth Sci, Milan, Italy..
    Barlassina, Cristina
    Univ Milan, Dept Hlth Sci, Milan, Italy..
    Bellis, Claire
    Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA.;Queensland Univ Technol, Inst Hlth & Biomed Innovat, Genom Res Ctr, Brisbane, Qld 4001, Australia..
    Benaglio, Paola
    Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA.;Univ Lausanne, Dept Med Genet, Lausanne, Switzerland..
    Blangero, John
    Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA..
    Blueher, Matthias
    Univ Leipzig, IFB Adipos Dis, D-04109 Leipzig, Germany.;Univ Leipzig, Dept Med, D-04109 Leipzig, Germany..
    Bonnet, Fabrice
    Univ Rennes 1, Rennes, France..
    Bonnycastle, Lori L.
    NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA..
    Boyd, Heather A.
    Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark..
    Bruinenberg, Marcel
    Univ Groningen, Univ Med Ctr Groningen, LifeLines Cohort Study, Groningen, Netherlands..
    Buchman, Aron S.
    Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA..
    Campbell, Harry
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Ctr Global Hlth Res, Edinburgh, Midlothian, Scotland..
    Chen, Yii-Der Ida
    Univ Calif Los Angeles, Med Ctr, Los Angeles BioMed Res Inst Harbor, Torrance, CA 90509 USA..
    Chines, Peter S.
    NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA..
    Claudi-Boehm, Simone
    Univ Ulm, Med Ctr, Dept Internal Med 1, D-89069 Ulm, Germany..
    Cole, John
    VA Maryland Hlth Care Syst, Baltimore, MD USA.;Univ Maryland, Sch Med, Dept Neurol, Baltimore, MD 21201 USA..
    Collins, Francis S.
    NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA..
    de Geus, Eco J. C.
    Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands.;Vrije Univ Amsterdam Med Ctr, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands..
    de Groot, Lisette C. P. G. M.
    Wageningen Univ, Dept Human Nutr, NL-6700 AP Wageningen, Netherlands..
    Dimitriou, Maria
    Wellcome Trust Sanger Inst, Human Genet, Cambridge, England.;Harokopio Univ, Dept Dietet Nutr, Athens, Greece..
    Duan, Jubao
    NorthShore Univ HealthSyst, Evanston, IL USA.;Univ Chicago, Chicago, IL 60637 USA..
    Enroth, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Eury, Elodie
    CNRS, UMR 8199, Lille, France.;European Genom Inst Diabet, Lille, France.;Univ Lille 2, Lille, France..
    Farmaki, Aliki-Eleni
    Harokopio Univ, Sch Hlth Sci & Educ, Dept Nutr & Dietet, Athens, Greece..
    Forouhi, Nita G.
    Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England..
    Friedrich, Nele
    Univ Med Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany..
    Gejman, Pablo V.
    NorthShore Univ HealthSyst, Evanston, IL USA.;Univ Chicago, Chicago, IL 60637 USA..
    Gigante, Bruna
    Karolinska Inst, Inst Environm Med, Div Cardiovasc Epidemiol, Stockholm, Sweden..
    Glorioso, Nicola
    AOU Univ Sassari, Hypertens & Related Dis Ctr, Sassari, Italy..
    Go, Alan S.
    Kaiser Permanente, Div Res, Oakland, CA USA..
    Gottesman, Omri
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Dept Med, New York, NY 10029 USA..
    Graessler, Juergen
    Univ Dresden, Dept Med Pathobiochem 3, Dresden, Germany..
    Grallert, Harald
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany.;German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany.;German Ctr Diabet Res DZD, Neuherberg, Germany..
    Grarup, Niels
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Genet, Copenhagen, Denmark..
    Gu, Yu-Mei
    Univ Leuven, KU Leuven Dept Cardiovasc Sci, Res Unit Hypertens & Cardiovasc Epidemiol, Leuven, Belgium..
    Broer, Linda
    Erasmus MC, Dept Internal Med, Rotterdam, Netherlands..
    Ham, Annelies C.
    Erasmus MC, Dept Internal Med, Rotterdam, Netherlands..
    Hansen, Torben
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Genet, Copenhagen, Denmark.;Univ Southern Denmark, Fac Hlth Sci, Odense, Denmark..
    Harris, Tamara B.
    NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA.;NIA, NIH, Bethesda, MD 20892 USA..
    Hartman, Catharina A.
    Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands..
    Hassinen, Maija
    Kuopio Res Inst Exercise Med, Kuopio, Finland..
    Hastie, Nicholas
    Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland..
    Hattersley, Andrew T.
    Univ Exeter, Inst Biomed & Clin Sci, Exeter, Devon, England..
    Heath, Andrew C.
    Washington Univ, Sch Med, St Louis, MO USA..
    Henders, Anjali K.
    QIMR Bergofer Med Res Inst, Brisbane, Qld, Australia..
    Hernandez, Dena
    NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA..
    Hillege, Hans
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands..
    Holmen, Oddgeir
    Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, N-7034 Trondheim, Norway..
    Hovingh, Kees G.
    Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands..
    Hui, Jennie
    Pathwest Lab Med Western Australia, Nedlands, WA, Australia.;Univ Western Australia, Sch Pathol & Lab Med, Nedlands, WA 6009, Australia.;Univ Western Australia, Sch Populat Hlth, Nedlands, WA 6009, Australia..
    Husemoen, Lise L.
    Glostrup Cty Hosp, Res Ctr Prevent & Hlth, Glostrup, Denmark..
    Hutri-Kahonen, Nina
    Univ Tampere, Sch Med, Dept Pediat, FIN-33101 Tampere, Finland.;Tampere Univ Hosp, Dept Pediat, Tampere, Finland..
    Hysi, Pirro G.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England..
    Illig, Thomas
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany.;Hannover Med Sch, Hannover Unified Biobank, Hannover, Germany.;Hannover Med Sch, Inst Human Genet, Hannover, NH, Germany..
    De Jager, Philip L.
    Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA.;Harvard Univ, Sch Med, Boston, MA 02115 USA.;Brigham & Womens Hosp, Dept Neurol, Program Translat NeuroPsychiat Genom, Boston, MA 02115 USA..
    Jalilzadeh, Shapour
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Div Cardiovac Med, Oxford, England..
    Jorgensen, Torben
    Glostrup Cty Hosp, Res Ctr Prevent & Hlth, Glostrup, Denmark.;Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark.;Aalborg Univ, Fac Med, Aalborg, Denmark..
    Jukema, J. Wouter
    Leiden Univ Med Ctr, Dept Cardiol, Leiden, Netherlands.;Interuniv Cardiol Inst Netherlands, Utrecht, Netherlands..
    Juonala, Markus
    Turku Univ Hosp, Div Med, FIN-20520 Turku, Finland.;Murdoch Childrens Res Inst, Parkville, Vic, Australia.;Univ Turku, Dept Med, Turku, Finland..
    Kanoni, Stavroula
    Wellcome Trust Sanger Inst, Human Genet, Cambridge, England.;Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England..
    Karaleftheri, Maria
    Echinos Med Ctr, Echinos, Greece..
    Khaw, Kay Tee
    Addenbrookes Hosp, Clin Gerontol Unit, Cambridge, England..
    Kinnunen, Leena
    Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland..
    Kittner, Steven J.
    VA Maryland Hlth Care Syst, Baltimore, MD USA.;Univ Maryland, Sch Med, Dept Neurol, Baltimore, MD 21201 USA..
    Koenig, Wolfgang
    Univ Ulm, Med Ctr, Dept Internal Med Cardiol 2, D-89069 Ulm, Germany..
    Kolcic, Ivana
    Univ Split, Fac Med, Dept Publ Hlth, Split, Croatia..
    Kovacs, Peter
    Univ Leipzig, IFB Adipos Dis, D-04109 Leipzig, Germany..
    Krarup, Nikolaj T.
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Genet, Copenhagen, Denmark..
    Kratzer, Wolfgang
    Univ Ulm, Med Ctr, Dept Internal Med 1, D-89069 Ulm, Germany..
    Krueger, Janine
    Univ Med Greifswald, Dept Med A, Greifswald, Germany..
    Kuh, Diana
    MRC Unit Lifelong Hlth & Ageing UCL, London, England..
    Kumari, Meena
    UCL, Dept Epidemiol & Publ Hlth, London, England..
    Kyriakou, Theodosios
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Div Cardiovac Med, Oxford, England..
    Langenberg, Claudia
    Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England.;UCL, Dept Epidemiol & Publ Hlth, London, England..
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lanzani, Chiara
    Univ Vita Salute San Raffaele, Chair Nephrol, Segrate, Milan, Italy.;IRCCS San Raffaele Sci Inst, Genom Renal Dis & Hypertens Unit, Segrate, Milan, Italy..
    Lotay, Vaneet
    Univ Calgary, Dept Biol Sci, Calgary, AB T2N 1N4, Canada..
    Launer, Lenore J.
    NIA, NIH, Bethesda, MD 20892 USA..
    Leander, Karin
    Karolinska Inst, Inst Environm Med, Div Cardiovasc Epidemiol, Stockholm, Sweden..
    Lindstrom, Jaana
    Natl Inst Hlth & Welf, Diabet Prevent Unit, Helsinki, Finland..
    Linneberg, Allan
    Glostrup Cty Hosp, Res Ctr Prevent & Hlth, Glostrup, Denmark.;Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark.;Rigshosp, Dept Clin Expt Res, Glostrup, Denmark..
    Liu, Yan-Ping
    Univ Leuven, KU Leuven Dept Cardiovasc Sci, Res Unit Hypertens & Cardiovasc Epidemiol, Leuven, Belgium..
    Lobbens, Stephane
    CNRS, UMR 8199, Lille, France.;European Genom Inst Diabet, Lille, France..
    Luben, Robert
    Strangeways Res Lab Worts Causeway, Cambridge, England..
    Lyssenko, Valeriya
    Steno Diabet Ctr A S, Gentofte, Denmark.;Lund Univ, Ctr Diabet, Malmo, Sweden.;Lund Univ, Dept Clin Sci, Diabet & Endocrinol Unit, Malmo, Sweden..
    Mannisto, Satu
    Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland..
    Magnusson, Patrik K.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    McArdle, Wendy L.
    Univ Bristol, Sch Social & Community Med, Bristol, Avon, England..
    Menni, Cristina
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England..
    Merger, Sigrun
    Univ Ulm, Med Ctr, Dept Internal Med 1, D-89069 Ulm, Germany..
    Milani, Lili
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia..
    Montgomery, Grant W.
    QIMR Bergofer Med Res Inst, Brisbane, Qld, Australia..
    Morris, Andrew P.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Liverpool, Dept Biostat, Liverpool L69 3BX, Merseyside, England..
    Narisu, Narisu
    NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA..
    Nelis, Mari
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia..
    Ong, Ken K.
    Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England.;MRC Unit Lifelong Hlth & Ageing UCL, London, England.;Univ Cambridge, Dept Paediat, Cambridge, England..
    Palotie, Aarno
    Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland.;Wellcome Trust Sanger Inst, Human Genet, Cambridge, England.;Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA.;Metaanal Glucose & Insulin Related Traits Consort, Beijing, Peoples R China..
    Perusse, Louis
    Univ Laval, Dept Kinesiol, Quebec City, PQ, Canada.;Univ Laval, Inst Nutr & Funct Foods, Quebec City, PQ, Canada..
    Pichler, Irene
    European Acad Bozen Bolzano EURAC, Ctr Biomed, Bolzano, Italy.;Med Univ Lubeck, Affiliated Inst, D-23538 Lubeck, Germany..
    Pilia, Maria G.
    CNR, Ist Ric Genet & Biomed, Monserrato, Italy..
    Pouta, Anneli
    Natl Inst Hlth & Welf, Dept Children Young People & Families, Helsinki, Finland.;Oulu Univ Hosp, Med Res Ctr, Dept Obstet & Gynecol, Oulu, Finland.;Univ Oulu, Oulu, Finland..
    Rheinberger, Myriam
    Univ Hosp Regensburg, Dept Nephrol, Regensburg, Germany..
    Ribel-Madsen, Rasmus
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Genet, Copenhagen, Denmark..
    Richards, Marcus
    MRC Unit Lifelong Hlth & Ageing UCL, London, England..
    Rice, Kenneth M.
    Univ Washington, Dept Biostat, Seattle, WA 98195 USA..
    Rice, Treva K.
    Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA.;Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA..
    Rivolta, Carlo
    Univ Lausanne, Dept Med Genet, Lausanne, Switzerland..
    Salomaa, Veikko
    Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland..
    Sanders, Alan R.
    NorthShore Univ HealthSyst, Evanston, IL USA.;Univ Chicago, Chicago, IL 60637 USA..
    Sarzynski, Mark A.
    Pennington Biomed Res Ctr, Human Genom Lab, Baton Rouge, LA 70808 USA..
    Scholtens, Salome
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands..
    Scott, Robert A.
    Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England..
    Scott, William R.
    Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London, England.;Ealing Hosp NHS Trust, Southall, Middx, England..
    Sebert, Sylvain
    Univ Oulu, Inst Hlth Sci, Oulu, Finland..
    Sengupta, Sebanti
    Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Sennblad, Bengt
    Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Stockholm, Sweden.;Karolinska Univ Hosp, Ctr Mol Med, Stockholm, Sweden.;Karolinska Inst, Sci Life Lab, Stockholm, Sweden..
    Seufferlein, Thomas
    Univ Ulm, Med Ctr, Dept Internal Med 1, D-89069 Ulm, Germany..
    Silveira, Angela
    Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Stockholm, Sweden.;Karolinska Univ Hosp, Ctr Mol Med, Stockholm, Sweden..
    Slagboom, P. Eline
    Leiden Univ Med Ctr, Dept Mol Epidemiol, Leiden, Netherlands..
    Smit, Jan H.
    Vrije Univ Amsterdam Med Ctr, Dept Psychiat, Amsterdam, Netherlands.;Vrije Univ Amsterdam Med Ctr, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands..
    Sparso, Thomas H.
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Genet, Copenhagen, Denmark..
    Stirrups, Kathleen
    Wellcome Trust Sanger Inst, Human Genet, Cambridge, England.;Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England..
    Stolk, Ronald P.
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands..
    Stringham, Heather M.
    Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Swertz, Morris A.
    Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands..
    Swift, Amy J.
    NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA..
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Tan, Sian-Tsung
    Ealing Hosp NHS Trust, Southall, Middx, England.;Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England..
    Thorand, Barbara
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany.;German Ctr Diabet Res DZD, Neuherberg, Germany..
    Toenjes, Anke
    Univ Leipzig, Dept Med, D-04109 Leipzig, Germany..
    Tremblay, Angelo
    Univ Laval, Dept Kinesiol, Quebec City, PQ, Canada..
    Tsafantakis, Emmanouil
    Anogia Med Ctr, Anogia, Greece..
    van der Most, Peter J.
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands..
    Voelker, Uwe
    Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany.;DZHK German Ctr Cardiovasc Res, Greifswald, Germany..
    Vohl, Marie-Claude
    Univ Laval, Inst Nutr & Funct Foods, Quebec City, PQ, Canada.;Univ Laval, Sch Nutr, Quebec City, PQ, Canada..
    Vonk, Judith M.
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands..
    Waldenberger, Melanie
    Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Munich, Germany.;German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany.;German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany..
    Walker, Ryan W.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Dept Prevent Med, New York, NY 10029 USA..
    Wennauer, Roman
    Univ Ulm, Med Ctr, Dept Clin Chem, D-89069 Ulm, Germany..
    Widen, Elisabeth
    Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland..
    Willemsen, Gonneke
    Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands..
    Wilsgaard, Tom
    Univ Tromso, Fac Hlth Sci, Dept Clin Med, Tromso, Norway.;Univ Tromso, Fac Hlth Sci, Dept Community Med, Tromso, Norway..
    Wright, Alan F.
    Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland..
    Zillikens, M. Carola
    NCHA, NGI, Leiden, Netherlands.;Erasmus MC, Dept Internal Med, Rotterdam, Netherlands..
    van Dijk, Suzanne C.
    Erasmus MC, Dept Internal Med, Rotterdam, Netherlands..
    van Schoor, Natasja M.
    Vrije Univ Amsterdam Med Ctr, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands.;Vrije Univ Amsterdam Med Ctr, Dept Epidemiol & Biostat, Amsterdam, Netherlands..
    Asselbergs, Folkert W.
    Univ Med Ctr Utrecht, Dept Cardiol, Div Heart & Lungs, Utrecht, Netherlands.;Netherlands Heart Inst, Interuniv Cardiol Inst Netherlands, Durrer Ctr Cardiogenet Res, Utrecht, Netherlands.;UCL, Inst Cardiovasc Sci, London, England..
    de Bakker, Paul I. W.
    Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands.;Univ Med Ctr, Dept Epidemiol, Utrecht, Netherlands..
    Beckmann, Jacques S.
    Swiss Inst Bioinformat, Lausanne, Switzerland..
    Beilby, John
    Pathwest Lab Med Western Australia, Nedlands, WA, Australia.;Univ Western Australia, Sch Pathol & Lab Med, Nedlands, WA 6009, Australia..
    Bennett, David A.
    Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA..
    Bergman, Richard N.
    Cedars Sinai Med Ctr, Diabet & Obes Res Inst, Los Angeles, CA 90048 USA..
    Bergmann, Sven
    Swiss Inst Bioinformat, Lausanne, Switzerland.;Univ Lausanne, Dept Med Genet, Lausanne, Switzerland..
    Boeger, Carsten A.
    Univ Hosp Regensburg, Dept Nephrol, Regensburg, Germany..
    Boehm, Bernhard O.
    Univ Ulm, Med Ctr, Dept Internal Med 1, D-89069 Ulm, Germany.;Univ London Imperial Coll Sci Technol & Med, London, England.;Lee Kong Chian Sch Med, Singapore, Singapore.;Nanyang Technol Univ, Singapore 639798, Singapore..
    Boerwinkle, Eric
    Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA.;Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA..
    Boomsma, Dorret I.
    Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands..
    Bornstein, Stefan R.
    Univ Dresden, Med Fac Carl Gustav Carus, Dept Med 3, Dresden, Germany..
    Bottinger, Erwin P.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Dept Med, New York, NY 10029 USA..
    Bouchard, Claude
    Pennington Biomed Res Ctr, Human Genom Lab, Baton Rouge, LA 70808 USA..
    Chambers, John C.
    Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London, England.;Ealing Hosp NHS Trust, Southall, Middx, England.;Imperial Coll Healthcare NHS Trust, London, England..
    Chanock, Stephen J.
    NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA.;Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Program Biostat & Biomath, Seattle, WA 98104 USA..
    Chasman, Daniel I.
    Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Boston, MA 02115 USA..
    Cucca, Francesco
    CNR, Ist Ric Genet & Biomed, Monserrato, Italy.;Univ Sassari, I-07100 Sassari, Italy..
    Cusi, Daniele
    Univ Milan, Dept Hlth Sci, Milan, Italy.;Natl Inst Res, Inst Biomed Technol, Segrate, Italy..
    Dedoussis, George
    Harokopio Univ, Sch Hlth Sci & Educ, Dept Nutr & Dietet, Athens, Greece..
    Erdmann, Jeanette
    Hamburg Kiel Lubeck, DZHK German Ctr Cardiovasc Res, Lubeck, Germany.;Univ Lubeck, Inst Integrat & Expt Genom, Lubeck, Germany..
    Eriksson, Johan G.
    Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland.;Folkhalsan Res Ctr, Helsinki, Finland.;Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland..
    Evans, Denis A.
    Rush Univ, Med Ctr, Rush Inst Healthy Aging, Chicago, IL 60612 USA.;Rush Univ, Med Ctr, Dept Internal Med, Chicago, IL 60612 USA..
    de Faire, Ulf
    Karolinska Inst, Inst Environm Med, Div Cardiovasc Epidemiol, Stockholm, Sweden..
    Farrall, Martin
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Div Cardiovac Med, Oxford, England.;Durrer Ctr Cardiogenet Res, Amsterdam, Netherlands..
    Ferrucci, Luigi
    NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA..
    Ford, Ian
    Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland..
    Franke, Lude
    Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands.;Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands..
    Franks, Paul W.
    Skane Univ Hosp Malmo, Dept Clin Sci, Genet & Mol Epidemiol Unit, Malmo, Sweden.;Umea Univ Hosp, Dept Publ Hlth & Clin Med, Umea, Sweden.;Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA..
    Froguel, Philippe
    CNRS, UMR 8199, Lille, France.;European Genom Inst Diabet, Lille, France.;Univ Lille 2, Lille, France..
    Gansevoort, Ron T.
    Univ Groningen, Univ Med Ctr Groningen, Dept Med, Groningen, Netherlands..
    Gieger, Christian
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany.;German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany..
    Gronberg, Henrik
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Gudnason, Vilmundur
    Iceland Heart Assoc, Kopavogur, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Hall, Per
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Hamsten, Anders
    Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Stockholm, Sweden.;Karolinska Univ Hosp, Ctr Mol Med, Stockholm, Sweden.;Karolinska Inst, Dept Med, Stockholm, Sweden..
    van der Harst, Pim
    Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands.;Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands.;Netherlands Heart Inst, Interuniv Cardiol Inst Netherlands, Durrer Ctr Cardiogenet Res, Utrecht, Netherlands..
    Hayward, Caroline
    Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland..
    Heliovaara, Markku
    Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland..
    Hengstenberg, Christian
    Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Munich, Germany.;Tech Univ Munich, Deutsch Herzzentrum Munchen, D-80290 Munich, Germany..
    Hicks, Andrew A.
    European Acad Bozen Bolzano EURAC, Ctr Biomed, Bolzano, Italy.;Med Univ Lubeck, Affiliated Inst, D-23538 Lubeck, Germany..
    Hingorani, Aroon
    UCL, Inst Cardiovasc Sci, London, England..
    Hofman, Albert
    NCHA, NGI, Leiden, Netherlands.;Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands..
    Hu, Frank
    Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA.;Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Boston, MA 02115 USA..
    Huikuri, Heikki V.
    Oulu Univ Hosp, Med Res Ctr Oulu, Oulu, Finland.;Univ Oulu, Oulu, Finland..
    Hveem, Kristian
    Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, N-7034 Trondheim, Norway..
    James, Alan L.
    Sir Charles Gairdner Hosp, Dept Pulm Physiol & Sleep Med, Nedlands, WA 6009, Australia..
    Jordan, Joanne M.
    Univ N Carolina Chapel Hill, Thurston Arthrit Res Ctr, Chaper Hill, NC USA..
    Jula, Antti
    Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland..
    Kaehoenen, Mika
    Tampere Univ Hosp, Dept Clin Physiol, Tampere, Finland.;Univ Tampere, Sch Med, Dept Clin Physiol, FIN-33101 Tampere, Finland..
    Kajantie, Eero
    Natl Inst Hlth & Welf, Diabet Prevent Unit, Helsinki, Finland.;Helsinki Univ Hosp, Childrens Hosp, Helsinki, Finland.;Univ Helsinki, Helsinki, Finland..
    Kathiresan, Sekar
    Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA.;Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA..
    Kiemeney, Lambertus A. L. M.
    Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Dept Hlth Evidence, NL-6525 ED Nijmegen, Netherlands.;Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Dept Urol, NL-6525 ED Nijmegen, Netherlands..
    Kivimaki, Mika
    UCL, Dept Epidemiol & Publ Hlth, London, England..
    Knekt, Paul B.
    Natl Inst Hlth & Welf, Helsinki, Finland..
    Koistinen, Heikki A.
    Natl Inst Hlth & Welf, Helsinki, Finland.;Univ Helsinki, Helsinki, Finland.;Helsinki Univ Cent Hosp, Dept Med, Helsinki, Finland.;Abdominal Ctr Endocrinol, Helsinki, Finland.;Minerva Fdn, Helsinki, Finland..
    Kooner, Jaspal S.
    Ealing Hosp NHS Trust, Southall, Middx, England.;Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England.;Imperial Coll Healthcare NHS Trust, London, England..
    Koskinen, Seppo
    Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland..
    Kuusisto, Johanna
    Univ Eastern Finland, Dept Med, Kuopio, Finland.;Kuopio Univ Hosp, SF-70210 Kuopio, Finland..
    Maerz, Winfried
    Heidelberg Univ, Mannheim Med Fac, Dept Med 5, Mannheim, Germany.;Med Univ Graz, Inst Clin Med, Graz, Austria.;Med Univ Graz, Chem Lab Diagnost, Graz, Austria..
    Martin, Nicholas G.
    QIMR Bergofer Med Res Inst, Brisbane, Qld, Australia..
    Laakso, Markku
    Univ Eastern Finland, Dept Med, Kuopio, Finland.;Kuopio Univ Hosp, SF-70210 Kuopio, Finland..
    Lakka, Timo A.
    Kuopio Res Inst Exercise Med, Kuopio, Finland.;Univ Eastern Finland, Inst Biomed, Dept Physiol, Kuopio, Finland..
    Lehtimaki, Terho
    Univ Tampere, Sch Med, Dept Clin Chem, FIN-33101 Tampere, Finland.;Univ Tampere, Dept Clin Chem, Fimlab Labs, FIN-33101 Tampere, Finland.;Univ Tampere, Sch Med, FIN-33101 Tampere, Finland..
    Lettre, Guillaume
    Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada.;Univ Montreal, Dept Med, Montreal, PQ H3C 3J7, Canada..
    Levinson, Douglas F.
    Stanford Univ, Stanford, CA 94305 USA..
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Lokki, Marja-Liisa
    Univ Helsinki, Transplantat Lab, Haartman Inst, Helsinki, Finland..
    Mantyselka, Pekka
    Univ Eastern Finland, Sch Med, Inst Publ Hlth & Clin Nutr, Primary Hlth Care Unit, Kuopio, Finland.;Kuopio Univ Hosp, Primary Hlth Care Unit, SF-70210 Kuopio, Finland..
    Melbye, Mads
    Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark.;Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark.;Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA..
    Metspalu, Andres
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia..
    Mitchell, Braxton D.
    Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA.;Baltimore Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD USA..
    Moll, Frans L.
    Univ Med Ctr Utrecht, Dept Surg, Utrecht, Netherlands..
    Murray, Jeffrey C.
    Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA..
    Musk, Arthur W.
    Sir Charles Gairdner Hosp, Dept Resp Med, Nedlands, WA 6009, Australia..
    Nieminen, Markku S.
    Helsinki Univ Cent Hosp, HUCH Heart & Lung Ctr, Div Cardiol, Helsinki, Finland..
    Njolstad, Inger
    Univ Tromso, Fac Hlth Sci, Dept Clin Med, Tromso, Norway.;Univ Tromso, Fac Hlth Sci, Dept Community Med, Tromso, Norway..
    Ohlsson, Claes
    Univ Gothenburg, Sahlgrenska Acad, Ctr Bone & Arthrit Res, Inst Med,Dept Internal Med & Clin Nutr, Gothenburg, Sweden..
    Oldehinkel, Albertine J.
    Univ Groningen, Univ Med Ctr, Interdisciplinary Ctr Psychopathol & Emot Regulat, Groningen, Netherlands..
    Oostra, Ben A.
    Erasmus MC, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands..
    Palmer, Lyle J.
    Univ Adelaide, Sch Publ Hlth, Adelaide, SA, Australia.;Univ Adelaide, Robinson Res Inst, Adelaide, SA, Australia..
    Pankow, James S.
    Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA..
    Pasterkamp, Gerard
    UMCU, Expt Cardiol & Lab Clin Chem, Utrecht, Netherlands..
    Pedersen, Nancy L.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Pedersen, Oluf
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Genet, Copenhagen, Denmark..
    Penninx, Brenda W.
    Vrije Univ Amsterdam Med Ctr, Dept Psychiat, Amsterdam, Netherlands.;Vrije Univ Amsterdam Med Ctr, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands..
    Perola, Markus
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia.;Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland.;Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland..
    Peters, Annette
    Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Munich, Germany.;German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany.;German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany..
    Polasek, Ozren
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Ctr Global Hlth Res, Edinburgh, Midlothian, Scotland.;Univ Split, Fac Med, Dept Publ Hlth, Split, Croatia..
    Pramstaller, Peter P.
    European Acad Bozen Bolzano EURAC, Ctr Biomed, Bolzano, Italy.;Med Univ Lubeck, Affiliated Inst, D-23538 Lubeck, Germany.;Gen Cent Hosp, Dept Neurol, Bolzano, Italy..
    Psaty, Bruce M.
    Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA.;Univ Washington, Dept Med, Seattle, WA 98195 USA.;Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA.;Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA.;Grp Hlth Cooperat, Grp Hlth Res Inst, Seatte, WA USA..
    Qi, Lu
    Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA.;Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Boston, MA 02115 USA..
    Quertermous, Thomas
    Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA..
    Raitakari, Olli T.
    Turku Univ Hosp, Dept Clin Physiol & Nucl Med, FIN-20520 Turku, Finland.;Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland..
    Rankinen, Tuomo
    Pennington Biomed Res Ctr, Human Genom Lab, Baton Rouge, LA 70808 USA..
    Rauramaa, Rainer
    Kuopio Res Inst Exercise Med, Kuopio, Finland.;Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, SF-70210 Kuopio, Finland..
    Ridker, Paul M.
    Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Boston, MA 02115 USA..
    Rioux, John D.
    Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada.;Univ Montreal, Dept Med, Montreal, PQ H3C 3J7, Canada..
    Rivadeneira, Fernando
    NCHA, NGI, Leiden, Netherlands.;Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.;Erasmus MC, Dept Internal Med, Rotterdam, Netherlands..
    Rotter, Jerome I.
    Univ Calif Los Angeles, Med Ctr, Los Angeles BioMed Res Inst Harbor, Torrance, CA 90509 USA..
    Rudan, Igor
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Ctr Global Hlth Res, Edinburgh, Midlothian, Scotland..
    den Ruijter, Hester M.
    UMCU, Expt Cardiol & Lab Clin Chem, Utrecht, Netherlands..
    Saltevo, Juha
    Cent Finland Cent Hosp, Dept Med, Jyvaskyla, Finland..
    Sattar, Naveed
    Univ Glasgow, BHF Glasgow Cardiovasc Res Ctr, Glasgow, Lanark, Scotland..
    Schunkert, Heribert
    Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Munich, Germany.;Tech Univ Munich, Deutsch Herzzentrum Munchen, D-80290 Munich, Germany..
    Schwarz, Peter E. H.
    Univ Dresden, Med Fac Carl Gustav Carus, Dept Med 3, Dresden, Germany..
    Shuldiner, Alan R.
    Univ Maryland, Sch Med, Dept Med, Div Endocrinol Diabet & Nutr,Program Personalized, Baltimore, MD 21201 USA.;Vetrans Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD USA..
    Sinisalo, Juha
    Helsinki Univ Cent Hosp, HUCH Heart & Lung Ctr, Div Cardiol, Helsinki, Finland..
    Snieder, Harold
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands..
    Sorensen, Thorkild I. A.
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Genet, Copenhagen, Denmark.;Univ Bristol, Sch Social & Community Med, MRC Integrat Epidemiol Unit, Bristol, Avon, England.;Bispebjerg & Frederiksberg Hosp, Inst Prevent Med, Frederiksberg, Denmark..
    Spector, Tim D.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England..
    Staessen, Jan A.
    Univ Leuven, KU Leuven Dept Cardiovasc Sci, Res Unit Hypertens & Cardiovasc Epidemiol, Leuven, Belgium.;Maastricht Univ, R&D VitaK Grp, Maastricht, Netherlands..
    Stefania, Bandinelli
    ASF, Geriatr Unit, Florence, Italy..
    Thorsteinsdottir, Unnur
    Amgen Inc, deCODE Genet, Reykjavik, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    Stumvoll, Michael
    Univ Leipzig, IFB Adipos Dis, D-04109 Leipzig, Germany.;Univ Leipzig, Dept Med, D-04109 Leipzig, Germany..
    Tardif, Jean-Claude
    Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada.;Univ Montreal, Dept Med, Montreal, PQ H3C 3J7, Canada..
    Tremoli, Elena
    IRCCS, Ctr Cardiol Monzino, Milan, Italy.;Univ Milan, Dipartimento Sci Farmacol & Biomol, Milan, Italy..
    Tuomilehto, Jaakko
    Natl Inst Hlth & Welf, Diabet Prevent Unit, Helsinki, Finland.;Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria.;Hosp Univ La Paz IdiPAZ, Inst Invest Sanitaria, Madrid, Spain.;King Abdulaziz Univ, Diabet Res Grp, Jeddah 21413, Saudi Arabia..
    Uitterlinden, Andre G.
    NCHA, NGI, Leiden, Netherlands.;Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.;Erasmus MC, Dept Internal Med, Rotterdam, Netherlands..
    Uusitupa, Matti
    Univ Eastern Finland, Dept Publ Hlth & Clin Nutr, Espoo, Finland.;Kuopio Univ Hosp, Res Unit, SF-70210 Kuopio, Finland..
    Verbeek, Andre L. M.
    Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Dept Hlth Evidence, NL-6525 ED Nijmegen, Netherlands..
    Vermeulen, Sita H.
    Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Dept Hlth Evidence, NL-6525 ED Nijmegen, Netherlands.;Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands..
    Viikari, Jorma S.
    Univ Turku, Dept Med, Turku, Finland..
    Vitart, Veronique
    Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland..
    Voelzke, Henry
    Univ Med Greifswald, Inst Community Med, Greifswald, Germany.;DZHK German Ctr Cardiovasc Res, Greifswald, Germany..
    Vollenweider, Peter
    Univ Hosp Lausanne CHUV, Dept Internal Med, Lausanne, Switzerland.;Univ Lausanne, Lausanne, Switzerland..
    Waeber, Gerard
    Univ Hosp Lausanne CHUV, Dept Internal Med, Lausanne, Switzerland.;Univ Lausanne, Lausanne, Switzerland..
    Walker, Mark
    Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA.;Newcastle Univ, Inst Cellular Med, Newcastle, NSW, Australia..
    Wallaschofski, Henri
    Univ Med Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany.;DZHK German Ctr Cardiovasc Res, Greifswald, Germany..
    Wareham, Nicholas J.
    Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England..
    Watkins, Hugh
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Div Cardiovac Med, Oxford, England..
    Zeggini, Eleftheria
    Wellcome Trust Sanger Inst, Human Genet, Cambridge, England..
    Chakravarti, Aravinda
    Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Ctr Complex Dis Genom, Baltimore, MD USA..
    Clegg, Deborah J.
    Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA..
    Cupples, L. Adrienne
    NHLBI, Framingham Heart Study, Framingham, MA USA.;Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA..
    Gordon-Larsen, Penny
    Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Nutr, Chapel Hill, NC USA.;Univ N Carolina, Carolina Populat Ctr, Chapel Hill, NC USA..
    Jaquish, Cashell E.
    NHLBI, NIH, Bethesda, MD 20892 USA..
    Rao, D. C.
    Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63110 USA.;Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA.;Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA..
    Abecasis, Goncalo R.
    Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Assimes, Themistocles L.
    Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA..
    Barroso, Ines
    Wellcome Trust Sanger Inst, Human Genet, Cambridge, England.;Addenbrookes Hosp, Inst Metab Sci, NIHR Cambridge Biomed Res Ctr, Cambridge, England.;Univ Cambridge, Addenbrookes Hosp, Inst Metab Sci, Metab Res Labs, Cambridge CB2 2QQ, England..
    Berndt, Sonja I.
    NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA..
    Boehnke, Michael
    Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Deloukas, Panos
    Wellcome Trust Sanger Inst, Human Genet, Cambridge, England.;Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England.;King Abdulaziz Univ, PACER HD, Jeddah 21413, Saudi Arabia..
    Fox, Caroline S.
    NHLBI, Framingham Heart Study, Framingham, MA USA.;Harvard Univ, Sch Med, Boston, MA 02115 USA..
    Groop, Leif C.
    Lund Univ, Ctr Diabet, Malmo, Sweden.;Lund Univ, Dept Clin Sci, Diabet & Endocrinol Unit, Malmo, Sweden.;Univ Helsinki, FIMM, Helsinki, Finland..
    Hunter, David J.
    MIT, Broad Inst, Cambridge, MA 02139 USA.;Harvard Univ, Cambridge, MA 02138 USA.;Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA.;Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Boston, MA 02115 USA.;Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA..
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA..
    Kaplan, Robert C.
    Albert Einstein Coll Med, Dept Epidemiol & Popualt Hlth, Bronx, NY 10467 USA..
    McCarthy, Mark I.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Oxford NIHR Biomed Res Ctr, Oxford, England..
    Mohlke, Karen L.
    Univ N Carolina, Dept Genet, Chapel Hill, NC USA..
    O'Connell, Jeffrey R.
    Univ Maryland, Sch Med, Dept Med, Div Endocrinol Diabet & Nutr,Program Personalized, Baltimore, MD 21201 USA..
    Schlessinger, David
    NIA, NIH, Bethesda, MD 20892 USA..
    Strachan, David P.
    St Georges Univ London, Populat Hlth Res Inst, London, England..
    Stefansson, Kari
    Amgen Inc, deCODE Genet, Reykjavik, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    van Duijn, Cornelia M.
    Erasmus MC, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands.;NCHA, NGI, Leiden, Netherlands.;Ctr Med Syst Biol, Leiden, Netherlands..
    Hirschhorn, Joel N.
    MIT, Broad Inst, Cambridge, MA 02139 USA.;Harvard Univ, Cambridge, MA 02138 USA.;Boston Childrens Hosp, Div Endocrinol, Boston, MA USA.;Boston Childrens Hosp, Div Genet, Boston, MA USA.;Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA..
    Lindgren, Cecilia M.
    MIT, Broad Inst, Cambridge, MA 02139 USA.;Harvard Univ, Cambridge, MA 02138 USA.;Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Heid, Iris M.
    Univ Regensburg, Inst Epidemiol & Prevent Med, Dept Genet Epidemiol, D-93053 Regensburg, Germany.;German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany..
    North, Kari E.
    Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC USA.;Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA..
    Borecki, Ingrid B.
    Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63110 USA..
    Kutalik, Zoltan
    Swiss Inst Bioinformat, Lausanne, Switzerland.;Univ Hosp Lausanne CHUV, Inst Social & Prevent Med, Lausanne, Switzerland.;Univ Lausanne, Dept Med Genet, Lausanne, Switzerland..
    Loos, Ruth J. F.
    Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England.;Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Dept Prevent Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA..
    The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study2015In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, no 10, article id e1005378Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age-and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to similar to 2.8M SNPs with BMI and WHRadjBMI in four strata (men <= 50y, men > 50y, women <= 50y, women > 50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR< 5%) age-specific effects, of which 11 had larger effects in younger (< 50y) than in older adults (>= 50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may providefurther insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.

  • 35.
    Xu, Dongqing
    et al.
    Peking Univ, Peking Tsinghua Ctr Life Sci, Sch Adv Agr Sci, State Key Lab Prot & Plant Gene Res, Beijing 100871, Peoples R China.;Peking Univ, Sch Life Sci, Beijing 100871, Peoples R China.;Gothenburg Univ, Dept Biol & Environm Sci, Gothenburg, Sweden..
    Lin, Fang
    Peking Univ, Peking Tsinghua Ctr Life Sci, Sch Adv Agr Sci, State Key Lab Prot & Plant Gene Res, Beijing 100871, Peoples R China.;Peking Univ, Sch Life Sci, Beijing 100871, Peoples R China..
    Jiang, Yan
    Peking Univ, Peking Tsinghua Ctr Life Sci, Sch Adv Agr Sci, State Key Lab Prot & Plant Gene Res, Beijing 100871, Peoples R China.;Peking Univ, Sch Life Sci, Beijing 100871, Peoples R China.;Gothenburg Univ, Dept Biol & Environm Sci, Gothenburg, Sweden..
    Ling, Junjie
    Peking Univ, Peking Tsinghua Ctr Life Sci, Sch Adv Agr Sci, State Key Lab Prot & Plant Gene Res, Beijing 100871, Peoples R China.;Peking Univ, Sch Life Sci, Beijing 100871, Peoples R China..
    Hettiarachchi, Chamari
    Univ Colombo, Dept Chem, Colombo, Sri Lanka..
    Tellgren-Roth, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Holm, Magnus
    Gothenburg Univ, Dept Biol & Environm Sci, Gothenburg, Sweden..
    Wei, Ning
    Yale Univ, Dept Mol Cellular & Dev Biol, New Haven, CT USA..
    Deng, Xing Wang
    Peking Univ, Peking Tsinghua Ctr Life Sci, Sch Adv Agr Sci, State Key Lab Prot & Plant Gene Res, Beijing 100871, Peoples R China.;Peking Univ, Sch Life Sci, Beijing 100871, Peoples R China..
    Arabidopsis COP1 SUPPRESSOR 2 Represses COP1 E3 Ubiquitin Ligase Activity through Their Coiled-Coil Domains Association2015In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, no 12, article id e1005747Article in journal (Refereed)
    Abstract [en]

    CONSTITUTIVE PHOTOMORPHOGENIC 1 (COP1) functions as an E3 ubiquitin ligase and mediates a variety of developmental processes in Arabidopsis by targeting a number of key regulators for ubiquitination and degradation. Here, we identify a novel COP1 interacting protein, COP1 SUPPRESSOR 2 (CSU2). Loss of function mutations in CSU2 suppress the constitutive photomorphogenic phenotype of cop1-6 in darkness. CSU2 directly interacts with COP1 via their coiled-coil domains and is recruited by COP1 into nuclear speckles in living plant cells. Furthermore, CSU2 inhibits COP1 E3 ubiquitin ligase activity in vitro, and represses COP1 mediated turnover of HY5 in cell-free extracts. We propose that in csu2 cop1-6 mutants, the lack of CSU2's repression of COP1 allows the low level of COP1 to exhibit higher activity that is sufficient to prevent accumulation of HY5 in the dark, thus restoring the etiolated phenotype. In addition, CSU2 is required for primary root development under normal light growth condition.

  • 36.
    Xu, Feifei
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jerlström-Hultqvist, Jon
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Einarsson, Elin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Astvaldsson, Asgeir
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Svärd, Staffan G
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Andersson, Jan O
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    The genome of Spironucleus salmonicida highlights a fish pathogen adapted to fluctuating environments2014In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 2, p. e1004053-Article in journal (Refereed)
    Abstract [en]

    Spironucleus salmonicida causes systemic infections in salmonid fish. It belongs to the group diplomonads, binucleated heterotrophic flagellates adapted to micro-aerobic environments. Recently we identified energy-producing hydrogenosomes in S. salmonicida. Here we present a genome analysis of the fish parasite with a focus on the comparison to the more studied diplomonad Giardia intestinalis. We annotated 8067 protein coding genes in the ∼12.9 Mbp S. salmonicida genome. Unlike G. intestinalis, promoter-like motifs were found upstream of genes which are correlated with gene expression, suggesting a more elaborate transcriptional regulation. S. salmonicida can utilise more carbohydrates as energy sources, has an extended amino acid and sulfur metabolism, and more enzymes involved in scavenging of reactive oxygen species compared to G. intestinalis. Both genomes have large families of cysteine-rich membrane proteins. A cluster analysis indicated large divergence of these families in the two diplomonads. Nevertheless, one of S. salmonicida cysteine-rich proteins was localised to the plasma membrane similar to G. intestinalis variant-surface proteins. We identified S. salmonicida homologs to cyst wall proteins and showed that one of these is functional when expressed in Giardia. This suggests that the fish parasite is transmitted as a cyst between hosts. The extended metabolic repertoire and more extensive gene regulation compared to G. intestinalis suggest that the fish parasite is more adapted to cope with environmental fluctuations. Our genome analyses indicate that S. salmonicida is a well-adapted pathogen that can colonize different sites in the host.

  • 37.
    Yang, Fan
    et al.
    Donnelly Ctr, Toronto, ON, Canada.;Univ Toronto, Dept Mol Genet, Toronto, ON, Canada.;Univ Toronto, Dept Comp Sci, Toronto, ON, Canada.;Sinai Hlth Syst, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada..
    Sun, Song
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Donnelly Ctr, Toronto, ON, Canada.;Univ Toronto, Dept Mol Genet, Toronto, ON, Canada.;Univ Toronto, Dept Comp Sci, Toronto, ON, Canada.;Sinai Hlth Syst, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada..
    Tan, Guihong
    Donnelly Ctr, Toronto, ON, Canada.;Univ Toronto, Dept Mol Genet, Toronto, ON, Canada..
    Costanzo, Michael
    Donnelly Ctr, Toronto, ON, Canada.;Univ Toronto, Dept Mol Genet, Toronto, ON, Canada..
    Hill, David E.
    Dana Farber Canc Inst, CCSB, Boston, MA 02115 USA.;Harvard Med Sch, Dept Genet, Boston, MA USA..
    Vidal, Marc
    Dana Farber Canc Inst, CCSB, Boston, MA 02115 USA.;Harvard Med Sch, Dept Genet, Boston, MA USA..
    Andrews, Brenda J.
    Donnelly Ctr, Toronto, ON, Canada.;Univ Toronto, Dept Mol Genet, Toronto, ON, Canada..
    Boone, Charles
    Donnelly Ctr, Toronto, ON, Canada.;Univ Toronto, Dept Mol Genet, Toronto, ON, Canada.;Canadian Inst Adv Res, Toronto, ON, Canada..
    Roth, Frederick P.
    Donnelly Ctr, Toronto, ON, Canada.;Univ Toronto, Dept Mol Genet, Toronto, ON, Canada.;Univ Toronto, Dept Comp Sci, Toronto, ON, Canada.;Sinai Hlth Syst, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada.;Dana Farber Canc Inst, CCSB, Boston, MA 02115 USA.;Canadian Inst Adv Res, Toronto, ON, Canada..
    Identifying pathogenicity of human variants via paralog-based yeast complementation2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 5, article id e1006779Article in journal (Refereed)
    Abstract [en]

    To better understand the health implications of personal genomes, we now face a largely unmet challenge to identify functional variants within disease-associated genes. Functional variants can be identified by trans-species complementation, e.g., by failure to rescue a yeast strain bearing a mutation in an orthologous human gene. Although orthologous complementation assays are powerful predictors of pathogenic variation, they are available for only a few percent of human disease genes. Here we systematically examine the question of whether complementation assays based on paralogy relationships can expand the number of human disease genes with functional variant detection assays. We tested over 1,000 paralogous human-yeast gene pairs for complementation, yielding 34 complementation relationships, of which 33 (97%) were novel. We found that paralog-based assays identified disease variants with success on par with that of orthology-based assays. Combining all homology-based assay results, we found that complementation can often identify pathogenic variants outside the homologous sequence region, presumably because of global effects on protein folding or stability. Within our search space, paralogy-based complementation more than doubled the number of human disease genes with a yeast-based complementation assay for disease variation.

  • 38. Zhai, Guangju
    et al.
    Teumer, Alexander
    Stolk, Lisette
    Perry, John R B
    Vandenput, Liesbeth
    Coviello, Andrea D
    Koster, Annemarie
    Bell, Jordana T
    Bhasin, Shalender
    Eriksson, Joel
    Eriksson, Anna
    Ernst, Florian
    Ferrucci, Luigi
    Frayling, Timothy M
    Glass, Daniel
    Grundberg, Elin
    Haring, Robin
    Hedman, Asa K
    Hofman, Albert
    Kiel, Douglas P
    Kroemer, Heyo K
    Liu, Yongmei
    Lunetta, Kathryn L
    Maggio, Marcello
    Lorentzon, Mattias
    Mangino, Massimo
    Melzer, David
    Miljkovic, Iva
    Nica, Alexandra
    Penninx, Brenda W J H
    Vasan, Ramachandran S
    Rivadeneira, Fernando
    Small, Kerrin S
    Soranzo, Nicole
    Uitterlinden, André G
    Völzke, Henry
    Wilson, Scott G
    Xi, Li
    Zhuang, Wei Vivian
    Harris, Tamara B
    Murabito, Joanne M
    Ohlsson, Claes
    Murray, Anna
    de Jong, Frank H
    Spector, Tim D
    Wallaschofski, Henri
    Eight common genetic variants associated with serum DHEAS levels suggest a key role in ageing mechanisms.2011In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 7, no 4Article in journal (Refereed)
    Abstract [en]

    Dehydroepiandrosterone sulphate (DHEAS) is the most abundant circulating steroid secreted by adrenal glands--yet its function is unknown. Its serum concentration declines significantly with increasing age, which has led to speculation that a relative DHEAS deficiency may contribute to the development of common age-related diseases or diminished longevity. We conducted a meta-analysis of genome-wide association data with 14,846 individuals and identified eight independent common SNPs associated with serum DHEAS concentrations. Genes at or near the identified loci include ZKSCAN5 (rs11761528; p = 3.15 × 10(-36)), SULT2A1 (rs2637125; p =  2.61 × 10(-19)), ARPC1A (rs740160; p =  1.56 × 10(-16)), TRIM4 (rs17277546; p =  4.50 × 10(-11)), BMF (rs7181230; p = 5.44 × 10(-11)), HHEX (rs2497306; p =  4.64 × 10(-9)), BCL2L11 (rs6738028; p = 1.72 × 10(-8)), and CYP2C9 (rs2185570; p = 2.29 × 10(-8)). These genes are associated with type 2 diabetes, lymphoma, actin filament assembly, drug and xenobiotic metabolism, and zinc finger proteins. Several SNPs were associated with changes in gene expression levels, and the related genes are connected to biological pathways linking DHEAS with ageing. This study provides much needed insight into the function of DHEAS.

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