uu.seUppsala University Publications
Change search
Refine search result
1 - 30 of 30
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 1. Allum, Fiona
    et al.
    Shao, Xiaojian
    Guénard, Frédéric
    Simon, Marie-Michelle
    Busche, Stephan
    Caron, Maxime
    Lambourne, John
    Lessard, Julie
    Tandre, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Hedman, Åsa K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kwan, Tony
    Ge, Bing
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    McCarthy, Mark I
    Deloukas, Panos
    Richmond, Todd
    Burgess, Daniel
    Spector, Timothy D
    Tchernof, André
    Marceau, Simon
    Lathrop, Mark
    Vohl, Marie-Claude
    Pastinen, Tomi
    Grundberg, Elin
    Characterization of functional methylomes by next-generation capture sequencing identifies novel disease-associated variants2015In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 6, article id 7211Article in journal (Refereed)
    Abstract [en]

    Most genome-wide methylation studies (EWAS) of multifactorial disease traits use targeted arrays or enrichment methodologies preferentially covering CpG-dense regions, to characterize sufficiently large samples. To overcome this limitation, we present here a new customizable, cost-effective approach, methylC-capture sequencing (MCC-Seq), for sequencing functional methylomes, while simultaneously providing genetic variation information. To illustrate MCC-Seq, we use whole-genome bisulfite sequencing on adipose tissue (AT) samples and public databases to design AT-specific panels. We establish its efficiency for high-density interrogation of methylome variability by systematic comparisons with other approaches and demonstrate its applicability by identifying novel methylation variation within enhancers strongly correlated to plasma triglyceride and HDL-cholesterol, including at CD36. Our more comprehensive AT panel assesses tissue methylation and genotypes in parallel at ∼4 and ∼3 M sites, respectively. Our study demonstrates that MCC-Seq provides comparable accuracy to alternative approaches but enables more efficient cataloguing of functional and disease-relevant epigenetic and genetic variants for large-scale EWAS.

  • 2. 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.

  • 3. Cho, Yoon Shin
    et al.
    Chen, Chien-Hsiun
    Hu, Cheng
    Long, Jirong
    Ong, Rick Twee Hee
    Sim, Xueling
    Takeuchi, Fumihiko
    Wu, Ying
    Go, Min Jin
    Yamauchi, Toshimasa
    Chang, Yi-Cheng
    Kwak, Soo Heon
    Ma, Ronald C W
    Yamamoto, Ken
    Adair, Linda S
    Aung, Tin
    Cai, Qiuyin
    Chang, Li-Ching
    Chen, Yuan-Tsong
    Gao, Yutang
    Hu, Frank B
    Kim, Hyung-Lae
    Kim, Sangsoo
    Kim, Young Jin
    Lee, Jeannette Jen-Mai
    Lee, Nanette R
    Li, Yun
    Liu, Jian Jun
    Lu, Wei
    Nakamura, Jiro
    Nakashima, Eitaro
    Ng, Daniel Peng-Keat
    Tay, Wan Ting
    Tsai, Fuu-Jen
    Wong, Tien Yin
    Yokota, Mitsuhiro
    Zheng, Wei
    Zhang, Rong
    Wang, Congrong
    So, Wing Yee
    Ohnaka, Keizo
    Ikegami, Hiroshi
    Hara, Kazuo
    Cho, Young Min
    Cho, Nam H
    Chang, Tien-Jyun
    Bao, Yuqian
    Hedman, Åsa K
    Morris, Andrew P
    McCarthy, Mark I
    Takayanagi, Ryoichi
    Park, Kyong Soo
    Jia, Weiping
    Chuang, Lee-Ming
    Chan, Juliana C N
    Maeda, Shiro
    Kadowaki, Takashi
    Lee, Jong-Young
    Wu, Jer-Yuarn
    Teo, Yik Ying
    Tai, E Shyong
    Shu, Xiao Ou
    Mohlke, Karen L
    Kato, Norihiro
    Han, Bok-Ghee
    Seielstad, Mark
    Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians.2012In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 44, no 1Article in journal (Refereed)
    Abstract [en]

    We conducted a three-stage genetic study to identify susceptibility loci for type 2 diabetes (T2D) in east Asian populations. We followed our stage 1 meta-analysis of eight T2D genome-wide association studies (6,952 cases with T2D and 11,865 controls) with a stage 2 in silico replication analysis (5,843 cases and 4,574 controls) and a stage 3 de novo replication analysis (12,284 cases and 13,172 controls). The combined analysis identified eight new T2D loci reaching genome-wide significance, which mapped in or near GLIS3, PEPD, FITM2-R3HDML-HNF4A, KCNK16, MAEA, GCC1-PAX4, PSMD6 and ZFAND3. GLIS3, which is involved in pancreatic beta cell development and insulin gene expression, is known for its association with fasting glucose levels. The evidence of an association with T2D for PEPD and HNF4A has been shown in previous studies. KCNK16 may regulate glucose-dependent insulin secretion in the pancreas. These findings, derived from an east Asian population, provide new perspectives on the etiology of T2D.

  • 4.
    Demerath, Ellen W.
    et al.
    Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN 55454 USA..
    Guan, Weihua
    Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55454 USA..
    Grove, Megan L.
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA..
    Aslibekyan, Stella
    Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA..
    Mendelson, Michael
    NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20824 USA.;Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.;Boston Childrens Hosp, Dept Cardiol, Boston, MA 02215 USA..
    Zhou, Yi-Hui
    N Carolina State Univ, Dept Stat, Raleigh, NC 27695 USA..
    Hedman, Åsa K.
    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..
    Sandling, Johanna K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Wellcome Trust Sanger Inst, Hinxton, England..
    Li, Li-An
    Irvin, Marguerite R.
    Zhi, Degui
    Univ Alabama Birmingham, Sch Publ Hlth, Dept Biostat, Birmingham, AL 35294 USA..
    Deloukas, Panos
    Wellcome Trust Sanger Inst, Hinxton, England.;Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England.;King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah 21589, Saudi Arabia..
    Liang, Liming
    NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20824 USA.;Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.;Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.;Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA..
    Liu, Chunyu
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.;Boston Univ, Dept Biostat, Boston, MA 02118 USA..
    Bressler, Jan
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA..
    Spector, Tim D.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England..
    North, Kari
    Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27514 USA..
    Li, Yun
    Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA.;Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA.;Univ N Carolina, Dept Comp Sci, Chapel Hill, NC 27599 USA..
    Absher, Devin M.
    Hudson Alpha Inst Biotechnol, Huntsville, AL 35806 USA..
    Levy, Daniel
    Arnett, Donna K.
    Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA..
    Fornage, Myriam
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA.;Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA..
    Pankow, James S.
    Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN 55454 USA..
    Boerwinkle, Eric
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA.;Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA..
    Epigenome-wide association study (EWAS) of BMI, BMI change and waist circumference in African American adults identifies multiple replicated loci2015In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 24, no 15, p. 4464-4479Article in journal (Refereed)
    Abstract [en]

    Obesity is an important component of the pathophysiology of chronic diseases. Identifying epigenetic modifications associated with elevated adiposity, including DNA methylation variation, may point to genomic pathways that are dysregulated in numerous conditions. The Illumina 450K Bead Chip array was used to assay DNA methylation in leukocyte DNA obtained from 2097 African American adults in the Atherosclerosis Risk in Communities (ARIC) study. Mixed-effects regression models were used to test the association of methylation beta value with concurrent body mass index (BMI) and waist circumference (WC), and BMI change, adjusting for batch effects and potential confounders. Replication using whole-blood DNA from 2377 White adults in the Framingham Heart Study and CD4+ T cell DNA from 991 Whites in the Genetics of Lipid Lowering Drugs and Diet Network Study was followed by testing using adipose tissue DNA from 648 women in the Multiple Tissue Human Expression Resource cohort. Seventy-six BMI-related probes, 164 WC-related probes and 8 BMI change-related probes passed the threshold for significance in ARIC (P < 1 x 10(-7); Bonferroni), including probes in the recently reported HIF3A, CPT1A and ABCG1 regions. Replication using blood DNA was achieved for 37 BMI probes and 1 additional WC probe. Sixteen of these also replicated in adipose tissue, including 15 novel methylation findings near genes involved in lipid metabolism, immune response/cytokine signaling and other diverse pathways, including LGALS3BP, KDM2B, PBX1 and BBS2, among others. Adiposity traits are associated with DNA methylation at numerous CpG sites that replicate across studies despite variation in tissue type, ethnicity and analytic approaches.

  • 5. Drong, Alexander W
    et al.
    Nicholson, George
    Hedman, Åsa K
    Meduri, Eshwar
    Grundberg, Elin
    Small, Kerrin S
    Shin, So-Youn
    Bell, Jordana T
    Karpe, Fredrik
    Soranzo, Nicole
    Spector, Tim D
    McCarthy, Mark I
    Deloukas, Panos
    Rantalainen, Mattias
    Lindgren, Cecilia M
    The presence of methylation quantitative trait loci indicates a direct genetic influence on the level of DNA methylation in adipose tissue.2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 2Article in journal (Refereed)
    Abstract [en]

    Genetic variants that associate with DNA methylation at CpG sites (methylation quantitative trait loci, meQTLs) offer a potential biological mechanism of action for disease associated SNPs. We investigated whether meQTLs exist in abdominal subcutaneous adipose tissue (SAT) and if CpG methylation associates with metabolic syndrome (MetSyn) phenotypes. We profiled 27,718 genomic regions in abdominal SAT samples of 38 unrelated individuals using differential methylation hybridization (DMH) together with genotypes at 5,227,243 SNPs and expression of 17,209 mRNA transcripts. Validation and replication of significant meQTLs was pursued in an independent cohort of 181 female twins. We find that, at 5% false discovery rate, methylation levels of 149 DMH regions associate with at least one SNP in a ±500 kilobase cis-region in our primary study. We sought to validate 19 of these in the replication study and find that five of these significantly associate with the corresponding meQTL SNPs from the primary study. We find that none of the 149 meQTL top SNPs is a significant expression quantitative trait locus in our expression data, but we observed association between expression levels of two mRNA transcripts and cis-methylation status. Our results indicate that DNA CpG methylation in abdominal SAT is partly under genetic control. This study provides a starting point for future investigations of DNA methylation in adipose tissue.

  • 6.
    Ek, Weronica E
    et al.
    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.
    Hedman, Åsa K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    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.
    Morris, Andrew P
    Lindgren, Cecilia M
    Mahajan, Anubha
    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.
    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.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    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.
    Genome-wide DNA methylation study identifies genes associated with the cardiovascular biomarker GDF-152016In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 25, no 4, p. 817-827Article in journal (Refereed)
    Abstract [en]

    Growth-differentiation factor 15 (GDF-15) is expressed in low to moderate levels in most healthy tissues and increases in response to inflammation. GDF-15 is associated with cardiovascular dysfunction and over-expressed in the myocardium of patients with myocardial infarction (MI). However, little is known about the function of GDF-15 in cardiovascular disease, and the underlying regulatory network of GDF-15 is not known. To investigate a possible association between GDF-15 levels and DNA methylation, we performed a genome-wide DNA methylation study of white blood cells in a population-based study (N = 717). Significant loci where replicated in an independent cohort (N = 963). We also performed a gene ontology (GO) enrichment analysis. We identified and replicated 16 CpG-sites (false discovery rate [FDR] < 0.05), at 11 independent loci including MIR21. MIR21 encodes a microRNA (miR-21) that has previously been shown to be associated with the development of heart disease. Interestingly, GDF15 mRNA contains a binding site for miR-21. Four sites were also differentially methylated in blood from participants previously diagnosed with MI and 14 enriched GO terms (FDR < 0.05, enrichment > 2) were identified, including 'cardiac muscle cell differentiation'. This study shows that GDF-15 levels are associated with differences in DNA methylation in blood cells, and a subset of the loci are also differentially methylated in participants with MI. However, there might be interactions between GDF-15 levels and methylation in other tissues not addressed in this study. These results provide novel links between GDF-15 and cardiovascular disease.

  • 7.
    Ek, Weronica E.
    et al.
    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.
    Tobi, Elmar W
    Ahsan, Muhammad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lampa, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Ponzi, Erica
    Kyrtopoulos, Soterios A
    Georgiadis, Panagiotis
    Lumey, L H
    Heijmans, Bastiaan T
    Botsivali, Maria
    Bergdahl, Ingvar A
    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.
    Rask-Andersen, Mathias
    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.
    Palli, Domenico
    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.
    Hedman, Åsa K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nilsson, Lena M
    Vineis, Paolo
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Flanagan, James M
    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.
    Tea and coffee consumption in relation to DNA methylation in four European cohorts2017In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 26, no 16, p. 3221-3231Article in journal (Refereed)
    Abstract [en]

    Lifestyle factors, such as food choices and exposure to chemicals, can alter DNA methylation and lead to changes in gene activity. Two such exposures with pharmacologically active components are coffee and tea consumption. Both coffee and tea have been suggested to play an important role in modulating disease-risk in humans by suppressing tumour progression, decreasing inflammation and influencing estrogen metabolism. These mechanisms may be mediated by changes in DNA methylation. To investigate if DNA methylation in blood is associated with coffee and tea consumption, we performed a genome-wide DNA methylation study for coffee and tea consumption in four European cohorts (N = 3,096). DNA methylation was measured from whole blood at 421,695 CpG sites distributed throughout the genome and analysed in men and women both separately and together in each cohort. Meta-analyses of the results and additional regional-level analyses were performed. After adjusting for multiple testing, the meta-analysis revealed that two individual CpG-sites, mapping to DNAJC16 and TTC17, were differentially methylated in relation to tea consumption in women. No individual sites were associated with men or with the sex-combined analysis for tea or coffee. The regional analysis revealed that 28 regions were differentially methylated in relation to tea consumption in women. These regions contained genes known to interact with estradiol metabolism and cancer. No significant regions were found in the sex-combined and male-only analysis for either tea or coffee consumption.

  • 8.
    Ganna, Andrea
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Salihovic, Samira
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Broeckling, Corey D
    Proteomics and Metabolomics Facility, Colorado State University, Fort Collins, Colorado, United States of America.
    Hedman, Åsa K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Magnusson, Patrik K E
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Pedersen, Nancy L
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Zilmer, Mihkel
    Department of Biochemistry, Centre of Excellence for Translational Medicine, University of Tartu, Tartu, Estonia.
    Prenni, Jessica
    Proteomics and Metabolomics Facility, Colorado State University, Fort Collins, Colorado, United States of America.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Large-scale Metabolomic Profiling Identifies Novel Biomarkers for Incident Coronary Heart Disease2014In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 12, p. e1004801-Article in journal (Refereed)
    Abstract [en]

    Analyses of circulating metabolites in large prospective epidemiological studies could lead to improved prediction and better biological understanding of coronary heart disease (CHD). We performed a mass spectrometry-based non-targeted metabolomics study for association with incident CHD events in 1,028 individuals (131 events; 10 y. median follow-up) with validation in 1,670 individuals (282 events; 3.9 y. median follow-up). Four metabolites were replicated and independent of main cardiovascular risk factors [lysophosphatidylcholine 18∶1 (hazard ratio [HR] per standard deviation [SD] increment = 0.77, P-value<0.001), lysophosphatidylcholine 18∶2 (HR = 0.81, P-value<0.001), monoglyceride 18∶2 (MG 18∶2; HR = 1.18, P-value = 0.011) and sphingomyelin 28∶1 (HR = 0.85, P-value = 0.015)]. Together they contributed to moderate improvements in discrimination and re-classification in addition to traditional risk factors (C-statistic: 0.76 vs. 0.75; NRI: 9.2%). MG 18∶2 was associated with CHD independently of triglycerides. Lysophosphatidylcholines were negatively associated with body mass index, C-reactive protein and with less evidence of subclinical cardiovascular disease in additional 970 participants; a reverse pattern was observed for MG 18∶2. MG 18∶2 showed an enrichment (P-value = 0.002) of significant associations with CHD-associated SNPs (P-value = 1.2×10-7 for association with rs964184 in the ZNF259/APOA5 region) and a weak, but positive causal effect (odds ratio = 1.05 per SD increment in MG 18∶2, P-value = 0.05) on CHD, as suggested by Mendelian randomization analysis. In conclusion, we identified four lipid-related metabolites with evidence for clinical utility, as well as a causal role in CHD development.

  • 9. Glass, Daniel
    et al.
    Viñuela, Ana
    Davies, Matthew N
    Ramasamy, Adaikalavan
    Parts, Leopold
    Knowles, David
    Brown, Andrew A
    Hedman, Åsa K
    Small, Kerrin S
    Buil, Alfonso
    Grundberg, Elin
    Nica, Alexandra C
    Di Meglio, Paola
    Nestle, Frank O
    Ryten, Mina
    Durbin, Richard
    McCarthy, Mark I
    Deloukas, Panagiotis
    Dermitzakis, Emmanouil T
    Weale, Michael E
    Bataille, Veronique
    Spector, Tim D
    Gene expression changes with age in skin, adipose tissue, blood and brain.2013In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 14, no 7Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Previous studies have demonstrated that gene expression levels change with age. These changes are hypothesized to influence the aging rate of an individual. We analyzed gene expression changes with age in abdominal skin, subcutaneous adipose tissue and lymphoblastoid cell lines in 856 female twins in the age range of 39-85 years. Additionally, we investigated genotypic variants involved in genotype-by-age interactions to understand how the genomic regulation of gene expression alters with age.

    RESULTS: Using a linear mixed model, differential expression with age was identified in 1,672 genes in skin and 188 genes in adipose tissue. Only two genes expressed in lymphoblastoid cell lines showed significant changes with age. Genes significantly regulated by age were compared with expression profiles in 10 brain regions from 100 postmortem brains aged 16 to 83 years. We identified only one age-related gene common to the three tissues. There were 12 genes that showed differential expression with age in both skin and brain tissue and three common to adipose and brain tissues.

    CONCLUSIONS: Skin showed the most age-related gene expression changes of all the tissues investigated, with many of the genes being previously implicated in fatty acid metabolism, mitochondrial activity, cancer and splicing. A significant proportion of age-related changes in gene expression appear to be tissue-specific with only a few genes sharing an age effect in expression across tissues. More research is needed to improve our understanding of the genetic influences on aging and the relationship with age-related diseases.

  • 10. Grundberg, Elin
    et al.
    Meduri, Eshwar
    Sandling, Johanna K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hedman, Åsa K.
    Wellcome Trust Centre for Human Genetics, University of Oxford, OX37BN Oxford, UK.
    Keildson, Sarah
    Buil, Alfonso
    Busche, Stephan
    Yuan, Wei
    Nisbet, James
    Sekowska, Magdalena
    Wilk, Alicja
    Barrett, Amy
    Small, Kerrin S.
    Ge, Bing
    Caron, Maxime
    Shin, So-Youn
    Lathrop, Mark
    Dermitzakis, Emmanouil T.
    McCarthy, Mark I.
    Spector, Timothy D.
    Bell, Jordana T.
    Deloukas, Panos
    Global Analysis of DNA Methylation Variation in Adipose Tissue from Twins Reveals Links to Disease-Associated Variants in Distal Regulatory Elements2013In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 93, no 5, p. 876-890Article in journal (Refereed)
    Abstract [en]

    Epigenetic modifications such as DNA methylation play a key role in gene regulation and disease susceptibility. However, little is known about the genome-wide frequency, localization, and function of methylation variation and how it is regulated by genetic and environmental factors. We utilized the Multiple Tissue Human Expression Resource (MuTHER) and generated Illumina 450K adipose methylome data from 648 twins. We found that individual CpGs had low variance and that variability was suppressed in promoters. We noted that DNA methylation variation was highly heritable (h(median)(2) = 0.34) and that shared environmental effects correlated with metabolic phenotype-associated CpGs. Analysis of methylation quantitative-trait loci (metQTL) revealed that 28% of CpGs were associated with nearby SNPs, and when overlapping them with adipose expression quantitative-trait loci (eQTL) from the same individuals, we found that 6% of the loci played a role in regulating both gene expression and DNA methylation. These associations were bidirectional, but there were pronounced negative associations for promoter CpGs. Integration of metQTL with adipose reference epigenomes and disease associations revealed significant enrichment of metQTL overlapping metabolic-trait or disease loci in enhancers (the strongest effects were for high-density lipoprotein cholesterol and body mass index [BMI]). We followed up with the BMI SNP rs713586, a cg01884057 metQTL that overlaps an enhancer upstream of ADCY3, and used bisulphite sequencing to refine this region. Our results showed widespread population invariability yet sequence dependence on adipose DNA methylation but that incorporating maps of regulatory elements aid in linking CpG variation to gene regulation and disease risk in a tissue-dependent manner.

  • 11. Grundberg, Elin
    et al.
    Small, Kerrin S
    Hedman, Åsa K
    Nica, Alexandra C
    Buil, Alfonso
    Keildson, Sarah
    Bell, Jordana T
    Yang, Tsun-Po
    Meduri, Eshwar
    Barrett, Amy
    Nisbett, James
    Sekowska, Magdalena
    Wilk, Alicja
    Shin, So-Youn
    Glass, Daniel
    Travers, Mary
    Min, Josine L
    Ring, Sue
    Ho, Karen
    Thorleifsson, Gudmar
    Kong, Augustine
    Thorsteindottir, Unnur
    Ainali, Chrysanthi
    Dimas, Antigone S
    Hassanali, Neelam
    Ingle, Catherine
    Knowles, David
    Krestyaninova, Maria
    Lowe, Christopher E
    Di Meglio, Paola
    Montgomery, Stephen B
    Parts, Leopold
    Potter, Simon
    Surdulescu, Gabriela
    Tsaprouni, Loukia
    Tsoka, Sophia
    Bataille, Veronique
    Durbin, Richard
    Nestle, Frank O
    O'Rahilly, Stephen
    Soranzo, Nicole
    Lindgren, Cecilia M
    Zondervan, Krina T
    Ahmadi, Kourosh R
    Schadt, Eric E
    Stefansson, Kari
    Smith, George Davey
    McCarthy, Mark I
    Deloukas, Panos
    Dermitzakis, Emmanouil T
    Spector, Tim D
    Mapping cis- and trans-regulatory effects across multiple tissues in twins.2012In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 44, no 10Article in journal (Refereed)
    Abstract [en]

    Sequence-based variation in gene expression is a key driver of disease risk. Common variants regulating expression in cis have been mapped in many expression quantitative trait locus (eQTL) studies, typically in single tissues from unrelated individuals. Here, we present a comprehensive analysis of gene expression across multiple tissues conducted in a large set of mono- and dizygotic twins that allows systematic dissection of genetic (cis and trans) and non-genetic effects on gene expression. Using identity-by-descent estimates, we show that at least 40% of the total heritable cis effect on expression cannot be accounted for by common cis variants, a finding that reveals the contribution of low-frequency and rare regulatory variants with respect to both transcriptional regulation and complex trait susceptibility. We show that a substantial proportion of gene expression heritability is trans to the structural gene, and we identify several replicating trans variants that act predominantly in a tissue-restricted manner and may regulate the transcription of many genes.

  • 12.
    Hedman, Asa K
    et al.
    Imperial College London, UK.
    Li, Ming-Shi
    Langford, Paul R
    Kroll, J Simon
    Transcriptional profiling of serogroup B Neisseria meningitidis growing in human blood: an approach to vaccine antigen discovery2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 6, p. e39718-Article in journal (Refereed)
  • 13.
    Hedman, Åsa K
    et al.
    Wellcome Trust Centre for Human Genetics, University of Oxford.
    Lindgren, Cecilia M
    McCarthy, Mark I
    Genome-Wide Association Studies of Obesity2014In: The Genetics of Obesity, Springer New York , 2014Chapter in book (Refereed)
  • 14.
    Hedman, Åsa K.
    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. Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden..
    Mendelson, Michael M.
    Framingham Heart Dis Epidemiol Study, Framingham, MA USA.;Boston Univ, Boston, MA 02215 USA.;Boston Childrens Hosp, Dept Cardiol, Boston, MA USA.;NHLBI, Populat Sci Branch, NIH, Bldg 10, Bethesda, MD 20892 USA..
    Marioni, Riccardo E.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9YL, Midlothian, Scotland.;Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Med Genet Sect, Edinburgh EH8 9YL, Midlothian, Scotland.;Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia..
    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.
    Joehanes, Roby
    Framingham Heart Dis Epidemiol Study, Framingham, MA USA.;NHLBI, Populat Sci Branch, NIH, Bldg 10, Bethesda, MD 20892 USA.;Harvard Med Sch, Hebrew Senior Life, Boston, MA USA..
    Irvin, Marguerite R.
    Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA..
    Zhi, Degui
    Univ Alabama Birmingham, Dept Biostat, Sect Stat Genet, Birmingham, AL 35294 USA..
    Sandling, Johanna K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Yao, Chen
    Framingham Heart Dis Epidemiol Study, Framingham, MA USA.;NHLBI, Populat Sci Branch, NIH, Bldg 10, Bethesda, MD 20892 USA..
    Liu, Chunyu
    Framingham Heart Dis Epidemiol Study, Framingham, MA USA.;Boston Univ, Dept Biosci, Boston, MA 02215 USA.;NHLBI, Populat Sci Branch, NIH, Bldg 10, Bethesda, MD 20892 USA..
    Liang, Liming
    Harvard Sch Publ Hlth, Dept Biostat, Boston, MA USA..
    Huan, Tianxiao
    Framingham Heart Dis Epidemiol Study, Framingham, MA USA.;NHLBI, Populat Sci Branch, NIH, Bldg 10, Bethesda, MD 20892 USA..
    McRae, Allan F.
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia.;Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Demissie, Serkalem
    Framingham Heart Dis Epidemiol Study, Framingham, MA USA.;Boston Univ, Dept Biosci, Boston, MA 02215 USA..
    Shah, Sonia
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia.;Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Starr, John M.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9YL, Midlothian, Scotland.;Univ Edinburgh, Alzheimer Scotland Dementia Res Ctr, Edinburgh EH8 9YL, Midlothian, Scotland..
    Cupples, L. Adrienne
    Framingham Heart Dis Epidemiol Study, Framingham, MA USA.;Boston Univ, Dept Biosci, Boston, MA 02215 USA..
    Deloukas, Panos
    Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England.;King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah, Saudi Arabia..
    Spector, Timothy D.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England..
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Krauss, Ronald M.
    Childrens Hosp Oakland, Res Inst, Oakland, CA 94609 USA..
    Arnett, Donna K.
    Univ Kentucky, Coll Publ Hlth, Lexington, KY 40506 USA..
    Deary, Ian J.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9YL, Midlothian, Scotland.;Univ Edinburgh, Dept Psychol, Edinburgh EH8 9YL, Midlothian, Scotland..
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Levy, Daniel
    Framingham Heart Dis Epidemiol Study, Framingham, MA USA.;NHLBI, Populat Sci Branch, NIH, Bldg 10, Bethesda, MD 20892 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, 300 Pasteur Dr,Mail Code 5773, Stanford, CA 94305 USA..
    Epigenetic Patterns in Blood Associated With Lipid Traits Predict Incident Coronary Heart Disease Events and Are Enriched for Results From Genome-Wide Association Studies2017In: Circulation: Cardiovascular Genetics, ISSN 1942-325X, E-ISSN 1942-3268, Vol. 10, no 1, article id UNSP e001487Article in journal (Refereed)
    Abstract [en]

    Background- Genome-wide association studies have identified loci influencing circulating lipid concentrations in humans; further information on novel contributing genes, pathways, and biology may be gained through studies of epigenetic modifications. Methods and Results- To identify epigenetic changes associated with lipid concentrations, we assayed genome-wide DNA methylation at cytosine-guanine dinucleotides (CpGs) in whole blood from 2306 individuals from 2 population-based cohorts, with replication of findings in 2025 additional individuals. We identified 193 CpGs associated with lipid levels in the discovery stage (P < 1.08E-07) and replicated 33 (at Bonferroni-corrected P < 0.05), including 25 novel CpGs not previously associated with lipids. Genes at lipid-associated CpGs were enriched in lipid and amino acid metabolism processes. A differentially methylated locus associated with triglyceridesand high-density lipoprotein cholesterol (HDL- C; cg27243685; P= 8.1E-26 and 9.3E-19) was associated with cis-expression of a reverse cholesterol transporter (ABCG1; P= 7.2E-28) and incident cardiovascular disease events (hazard ratio per SD increment, 1.38; 95% confidence interval, 1.15-1.66; P= 0.0007). We found significant cis-methylation quantitative trait loci at 64% of the 193 CpGs with an enrichment of signals from genome-wide association studies of lipid levels (P-TC = 0.004, PHDL-C = 0.008 and P-triglycerides = 0.00003) and coronary heart disease ( P= 0.0007). For example, genome-wide significant variants associated with low-density lipoprotein cholesterol and coronary heart disease at APOB were cis-methylation quantitative trait loci for a low-density lipoprotein cholesterol-related differentially methylated locus. Conclusions-We report novel associations of DNA methylation with lipid levels, describe epigenetic mechanisms related to previous genome-wide association studies discoveries, and provide evidence implicating epigenetic regulation of reverse cholesterol transport in blood in relation to occurrence of cardiovascular disease events.

  • 15.
    Hedman, Åsa K.
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Zilmer, Mihkel
    Univ Tartu, Inst Biomed & Translat Med, Dept Biochem, Ctr Excellence Genom & Translat Med, Tartu, Estonia..
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Lind, Lars
    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, Cardiovascular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA..
    DNA methylation patterns associated with oxidative stress in an ageing population2016In: BMC Medical Genomics, ISSN 1755-8794, E-ISSN 1755-8794, Vol. 9, article id 72Article in journal (Refereed)
    Abstract [en]

    Background: Oxidative stress has been related to type 2 diabetes (T2D) and cardiovascular disease (CVD), the leading global cause of death. Contributions of environmental factors such as oxidative stress on complex traits and disease may be partly mediated through changes in epigenetic marks (e.g. DNA methylation). Studies relating differential methylation with intermediate phenotypes and disease endpoints may be useful in identifying additional candidate genes and mechanisms involved in disease. Methods: To investigate the role of epigenetic variation in oxidative stress marker levels and subsequent development of CVD and T2D, we performed analyses of genome-wide DNA methylation in blood, ten markers of oxidative stress (total glutathione [TGSH], reduced glutathione [GSH], oxidised glutathione [GSSG], GSSG to GSH ratio, homocysteine [HCY], oxidised low-density lipoprotein (oxLDL), antibodies against oxLDL [OLAB], conjugated dienes [CD], baseline conjugated dienes [BCD]-LDL and total antioxidant capacity [TAOC]) and incident disease in up to 966 age-matched individuals. Results: In total, we found 66 cytosine-guanine (CpG) sites associated with one or more oxidative stress markers (false discovery rate [FDR] <0.05). These sites were enriched in regulatory regions of the genome. Genes annotated to CpG sites showed enrichment in annotation clusters relating to phospho-metabolism and proteins with pleckstrin domains. We investigated the contribution of oxidative stress-associated CpGs to development of cardiometabolic disease. Methylation variation at CpGs in the 3'-UTR of HIST1H4D (cg08170869; histone cluster 1, H4d) and in the body of DVL1 (cg03465880; dishevelled-1) were associated with incident T2D events during 10 years of follow-up (all permutation p-values < 0.01), indicating a role of epigenetic regulation in oxidative stress processes leading to development or progression of diabetes. Methylation QTL (meQTL) analysis showed significant associations with genetic sequence variants in cis at 28 (42%) of oxidative stress phenotype-associated sites (FDR < 0.05). Integrating cis-meQTLs with genotype-phenotype associations indicated that genetic effects on oxidative stress phenotype at one locus (cg07547695; BCL2L11) may be mediated through DNA methylation. Conclusions: In conclusion, we report novel associations of DNA methylation with oxidative stress, some of which also show evidence of a relation with T2D incidence.

  • 16. Keildson, Sarah
    et al.
    Fadista, Joao
    Ladenvall, Claes
    Hedman, Åsa K
    Elgzyri, Targ
    Small, Kerrin S
    Grundberg, Elin
    Nica, Alexandra C
    Glass, Daniel
    Richards, J Brent
    Barrett, Amy
    Nisbet, James
    Zheng, Hou-Feng
    Rönn, Tina
    Ström, Kristoffer
    Eriksson, Karl-Fredrik
    Prokopenko, Inga
    Spector, Timothy D
    Dermitzakis, Emmanouil T
    Deloukas, Panos
    McCarthy, Mark I
    Rung, Johan
    Groop, Leif
    Franks, Paul W
    Lindgren, Cecilia M
    Hansson, Ola
    Expression of phosphofructokinase in skeletal muscle is influenced by genetic variation and associated with insulin sensitivity.2014In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 63, no 3Article in journal (Refereed)
    Abstract [en]

    Using an integrative approach in which genetic variation, gene expression, and clinical phenotypes are assessed in relevant tissues may help functionally characterize the contribution of genetics to disease susceptibility. We sought to identify genetic variation influencing skeletal muscle gene expression (expression quantitative trait loci [eQTLs]) as well as expression associated with measures of insulin sensitivity. We investigated associations of 3,799,401 genetic variants in expression of >7,000 genes from three cohorts (n = 104). We identified 287 genes with cis-acting eQTLs (false discovery rate [FDR] <5%; P < 1.96 × 10(-5)) and 49 expression-insulin sensitivity phenotype associations (i.e., fasting insulin, homeostasis model assessment-insulin resistance, and BMI) (FDR <5%; P = 1.34 × 10(-4)). One of these associations, fasting insulin/phosphofructokinase (PFKM), overlaps with an eQTL. Furthermore, the expression of PFKM, a rate-limiting enzyme in glycolysis, was nominally associated with glucose uptake in skeletal muscle (P = 0.026; n = 42) and overexpressed (Bonferroni-corrected P = 0.03) in skeletal muscle of patients with T2D (n = 102) compared with normoglycemic controls (n = 87). The PFKM eQTL (rs4547172; P = 7.69 × 10(-6)) was nominally associated with glucose uptake, glucose oxidation rate, intramuscular triglyceride content, and metabolic flexibility (P = 0.016-0.048; n = 178). We explored eQTL results using published data from genome-wide association studies (DIAGRAM and MAGIC), and a proxy for the PFKM eQTL (rs11168327; r(2) = 0.75) was nominally associated with T2D (DIAGRAM P = 2.7 × 10(-3)). Taken together, our analysis highlights PFKM as a potential regulator of skeletal muscle insulin sensitivity.

  • 17. Kilpeläinen, Tuomas O
    et al.
    Carli, Jayne F Martin
    Skowronski, Alicja A
    Sun, Qi
    Kriebel, Jennifer
    Feitosa, Mary F
    Hedman, Åsa K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Drong, Alexander W
    Hayes, James E
    Zhao, Jinghua
    Pers, Tune H
    Schick, Ursula
    Grarup, Niels
    Kutalik, Zoltán
    Trompet, Stella
    Mangino, Massimo
    Kristiansson, Kati
    Beekman, Marian
    Lyytikäinen, Leo-Pekka
    Eriksson, Joel
    Henneman, Peter
    Lahti, Jari
    Tanaka, Toshiko
    Luan, Jian'an
    Greco M, Fabiola Del
    Pasko, Dorota
    Renström, Frida
    Willems, Sara M
    Mahajan, Anubha
    Rose, Lynda M
    Guo, Xiuqing
    Liu, Yongmei
    Kleber, Marcus E
    Pérusse, Louis
    Gaunt, Tom
    Ahluwalia, Tarunveer S
    Ju Sung, Yun
    Ramos, Yolande F
    Amin, Najaf
    Amuzu, Antoinette
    Barroso, Inês
    Bellis, Claire
    Blangero, John
    Buckley, Brendan M
    Böhringer, Stefan
    I Chen, Yii-Der
    de Craen, Anton J N
    Crosslin, David R
    Dale, Caroline E
    Dastani, Zari
    Day, Felix R
    Deelen, Joris
    Delgado, Graciela E
    Demirkan, Ayse
    Finucane, Francis M
    Ford, Ian
    Garcia, Melissa E
    Gieger, Christian
    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.
    Hallmans, Göran
    Hankinson, Susan E
    Havulinna, Aki S
    Herder, Christian
    Hernandez, Dena
    Hicks, Andrew A
    Hunter, David J
    Illig, Thomas
    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.
    Ioan-Facsinay, Andreea
    Jansson, John-Olov
    Jenny, Nancy S
    Jørgensen, Marit E
    Jørgensen, Torben
    Karlsson, Magnus
    Koenig, Wolfgang
    Kraft, Peter
    Kwekkeboom, Joanneke
    Laatikainen, Tiina
    Ladwig, Karl-Heinz
    LeDuc, Charles A
    Lowe, Gordon
    Lu, Yingchang
    Marques-Vidal, Pedro
    Meisinger, Christa
    Menni, Cristina
    Morris, Andrew P
    Myers, Richard H
    Männistö, Satu
    Nalls, Mike A
    Paternoster, Lavinia
    Peters, Annette
    Pradhan, Aruna D
    Rankinen, Tuomo
    Rasmussen-Torvik, Laura J
    Rathmann, Wolfgang
    Rice, Treva K
    Brent Richards, J
    Ridker, Paul M
    Sattar, Naveed
    Savage, David B
    Söderberg, Stefan
    Timpson, Nicholas J
    Vandenput, Liesbeth
    van Heemst, Diana
    Uh, Hae-Won
    Vohl, Marie-Claude
    Walker, Mark
    Wichmann, Heinz-Erich
    Widén, Elisabeth
    Wood, Andrew R
    Yao, Jie
    Zeller, Tanja
    Zhang, Yiying
    Meulenbelt, Ingrid
    Kloppenburg, Margreet
    Astrup, Arne
    Sørensen, Thorkild I A
    Sarzynski, Mark A
    Rao, D C
    Jousilahti, Pekka
    Vartiainen, Erkki
    Hofman, Albert
    Rivadeneira, Fernando
    Uitterlinden, André G
    Kajantie, Eero
    Osmond, Clive
    Palotie, Aarno
    Eriksson, Johan G
    Heliövaara, Markku
    Knekt, Paul B
    Koskinen, Seppo
    Jula, Antti
    Perola, Markus
    Huupponen, Risto K
    Viikari, Jorma S
    Kähönen, Mika
    Lehtimäki, Terho
    Raitakari, Olli T
    Mellström, Dan
    Lorentzon, Mattias
    Casas, Juan P
    Bandinelli, Stefanie
    März, Winfried
    Isaacs, Aaron
    van Dijk, Ko W
    van Duijn, Cornelia M
    Harris, Tamara B
    Bouchard, Claude
    Allison, Matthew A
    Chasman, Daniel I
    Ohlsson, Claes
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Scott, Robert A
    Langenberg, Claudia
    Wareham, Nicholas J
    Ferrucci, Luigi
    Frayling, Timothy M
    Pramstaller, Peter P
    Borecki, Ingrid B
    Waterworth, Dawn M
    Bergmann, Sven
    Waeber, Gérard
    Vollenweider, Peter
    Vestergaard, Henrik
    Hansen, Torben
    Pedersen, Oluf
    Hu, Frank B
    Eline Slagboom, P
    Grallert, Harald
    Spector, Tim D
    Jukema, J W
    Klein, Robert J
    Schadt, Erik E
    Franks, Paul W
    Lindgren, Cecilia M
    Leibel, Rudolph L
    Loos, Ruth J F
    Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels2016In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, article id 10494Article in journal (Refereed)
    Abstract [en]

    Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.

  • 18. Kooner, Jaspal S
    et al.
    Saleheen, Danish
    Sim, Xueling
    Sehmi, Joban
    Zhang, Weihua
    Frossard, Philippe
    Been, Latonya F
    Chia, Kee-Seng
    Dimas, Antigone S
    Hassanali, Neelam
    Jafar, Tazeen
    Jowett, Jeremy B M
    Li, Xinzhong
    Radha, Venkatesan
    Rees, Simon D
    Takeuchi, Fumihiko
    Young, Robin
    Aung, Tin
    Basit, Abdul
    Chidambaram, Manickam
    Das, Debashish
    Grundberg, Elin
    Hedman, Asa K
    Hydrie, Zafar I
    Islam, Muhammed
    Khor, Chiea-Chuen
    Kowlessur, Sudhir
    Kristensen, Malene M
    Liju, Samuel
    Lim, Wei-Yen
    Matthews, David R
    Liu, Jianjun
    Morris, Andrew P
    Nica, Alexandra C
    Pinidiyapathirage, Janani M
    Prokopenko, Inga
    Rasheed, Asif
    Samuel, Maria
    Shah, Nabi
    Shera, A Samad
    Small, Kerrin S
    Suo, Chen
    Wickremasinghe, Ananda R
    Wong, Tien Yin
    Yang, Mingyu
    Zhang, Fan
    Abecasis, Goncalo R
    Barnett, Anthony H
    Caulfield, Mark
    Deloukas, Panos
    Frayling, Timothy M
    Froguel, Philippe
    Kato, Norihiro
    Katulanda, Prasad
    Kelly, M Ann
    Liang, Junbin
    Mohan, Viswanathan
    Sanghera, Dharambir K
    Scott, James
    Seielstad, Mark
    Zimmet, Paul Z
    Elliott, Paul
    Teo, Yik Ying
    McCarthy, Mark I
    Danesh, John
    Tai, E Shyong
    Chambers, John C
    Genome-wide association study in individuals of South Asian ancestry identifies six new type 2 diabetes susceptibility loci.2011In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 43, no 10Article in journal (Refereed)
    Abstract [en]

    We carried out a genome-wide association study of type-2 diabetes (T2D) in individuals of South Asian ancestry. Our discovery set included 5,561 individuals with T2D (cases) and 14,458 controls drawn from studies in London, Pakistan and Singapore. We identified 20 independent SNPs associated with T2D at P < 10(-4) for testing in a replication sample of 13,170 cases and 25,398 controls, also all of South Asian ancestry. In the combined analysis, we identified common genetic variants at six loci (GRB14, ST6GAL1, VPS26A, HMG20A, AP3S2 and HNF4A) newly associated with T2D (P = 4.1 × 10(-8) to P = 1.9 × 10(-11)). SNPs at GRB14 were also associated with insulin sensitivity (P = 5.0 × 10(-4)), and SNPs at ST6GAL1 and HNF4A were also associated with pancreatic beta-cell function (P = 0.02 and P = 0.001, respectively). Our findings provide additional insight into mechanisms underlying T2D and show the potential for new discovery from genetic association studies in South Asians, a population with increased susceptibility to T2D.

  • 19. Locke, Adam E
    et al.
    Kahali, Bratati
    Berndt, Sonja I
    Justice, Anne E
    Pers, Tune H
    Day, Felix R
    Powell, Corey
    Vedantam, Sailaja
    Buchkovich, Martin L
    Yang, Jian
    Croteau-Chonka, Damien C
    Esko, Tonu
    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.
    Ferreira, Teresa
    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.
    Kutalik, Zoltán
    Luan, Jian'an
    Mägi, Reedik
    Randall, Joshua C
    Winkler, Thomas W
    Wood, Andrew R
    Workalemahu, Tsegaselassie
    Faul, Jessica D
    Smith, Jennifer A
    Hua Zhao, Jing
    Zhao, Wei
    Chen, Jin
    Fehrmann, Rudolf
    Hedman, Åsa K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Karjalainen, Juha
    Schmidt, Ellen M
    Absher, Devin
    Amin, Najaf
    Anderson, Denise
    Beekman, Marian
    Bolton, Jennifer L
    Bragg-Gresham, Jennifer L
    Buyske, Steven
    Demirkan, Ayse
    Deng, Guohong
    Ehret, Georg B
    Feenstra, Bjarke
    Feitosa, Mary F
    Fischer, Krista
    Goel, Anuj
    Gong, Jian
    Jackson, Anne U
    Kanoni, Stavroula
    Kleber, Marcus E
    Kristiansson, Kati
    Lim, Unhee
    Lotay, Vaneet
    Mangino, Massimo
    Mateo Leach, Irene
    Medina-Gomez, Carolina
    Medland, Sarah E
    Nalls, Michael A
    Palmer, Cameron D
    Pasko, Dorota
    Pechlivanis, Sonali
    Peters, Marjolein J
    Prokopenko, Inga
    Shungin, Dmitry
    Stančáková, Alena
    Strawbridge, Rona J
    Ju Sung, Yun
    Tanaka, Toshiko
    Teumer, Alexander
    Trompet, Stella
    van der Laan, Sander W
    van Setten, Jessica
    Van Vliet-Ostaptchouk, Jana V
    Wang, Zhaoming
    Yengo, Loïc
    Zhang, Weihua
    Isaacs, Aaron
    Albrecht, Eva
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Arscott, Gillian M
    Attwood, Antony P
    Bandinelli, Stefania
    Barrett, Amy
    Bas, Isabelita N
    Bellis, Claire
    Bennett, Amanda J
    Berne, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Blagieva, Roza
    Blüher, Matthias
    Böhringer, Stefan
    Bonnycastle, Lori L
    Böttcher, Yvonne
    Boyd, Heather A
    Bruinenberg, Marcel
    Caspersen, Ida H
    Ida Chen, Yii-Der
    Clarke, Robert
    Warwick Daw, E
    de Craen, Anton J M
    Delgado, Graciela
    Dimitriou, Maria
    Doney, Alex S F
    Eklund, Niina
    Estrada, Karol
    Eury, Elodie
    Folkersen, Lasse
    Fraser, Ross M
    Garcia, Melissa E
    Geller, Frank
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Gigante, Bruna
    Go, Alan S
    Golay, Alain
    Goodall, Alison H
    Gordon, Scott D
    Gorski, Mathias
    Grabe, Hans-Jörgen
    Grallert, Harald
    Grammer, Tanja B
    Gräßler, Jürgen
    Grönberg, Henrik
    Groves, Christopher J
    Gusto, Gaëlle
    Haessler, Jeffrey
    Hall, Per
    Haller, Toomas
    Hallmans, Goran
    Hartman, Catharina A
    Hassinen, Maija
    Hayward, Caroline
    Heard-Costa, Nancy L
    Helmer, Quinta
    Hengstenberg, Christian
    Holmen, Oddgeir
    Hottenga, Jouke-Jan
    James, Alan L
    Jeff, Janina M
    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.
    Jolley, Jennifer
    Juliusdottir, Thorhildur
    Kinnunen, Leena
    Koenig, Wolfgang
    Koskenvuo, Markku
    Kratzer, Wolfgang
    Laitinen, Jaana
    Lamina, Claudia
    Leander, Karin
    Lee, Nanette R
    Lichtner, Peter
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Lindström, Jaana
    Sin Lo, Ken
    Lobbens, Stéphane
    Lorbeer, Roberto
    Lu, Yingchang
    Mach, François
    Magnusson, Patrik K E
    Mahajan, Anubha
    McArdle, Wendy L
    McLachlan, Stela
    Menni, Cristina
    Merger, Sigrun
    Mihailov, Evelin
    Milani, Lili
    Moayyeri, Alireza
    Monda, Keri L
    Morken, Mario A
    Mulas, Antonella
    Müller, Gabriele
    Müller-Nurasyid, Martina
    Musk, Arthur W
    Nagaraja, Ramaiah
    Nöthen, Markus M
    Nolte, Ilja M
    Pilz, Stefan
    Rayner, Nigel W
    Renstrom, Frida
    Rettig, Rainer
    Ried, Janina S
    Ripke, Stephan
    Robertson, Neil R
    Rose, Lynda M
    Sanna, Serena
    Scharnagl, Hubert
    Scholtens, Salome
    Schumacher, Fredrick R
    Scott, William R
    Seufferlein, Thomas
    Shi, Jianxin
    Vernon Smith, Albert
    Smolonska, Joanna
    Stanton, Alice V
    Steinthorsdottir, Valgerdur
    Stirrups, Kathleen
    Stringham, Heather M
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Swertz, Morris A
    Swift, Amy J
    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.
    Tan, Sian-Tsung
    Tayo, Bamidele O
    Thorand, Barbara
    Thorleifsson, Gudmar
    Tyrer, Jonathan P
    Uh, Hae-Won
    Vandenput, Liesbeth
    Verhulst, Frank C
    Vermeulen, Sita H
    Verweij, Niek
    Vonk, Judith M
    Waite, Lindsay L
    Warren, Helen R
    Waterworth, Dawn
    Weedon, Michael N
    Wilkens, Lynne R
    Willenborg, Christina
    Wilsgaard, Tom
    Wojczynski, Mary K
    Wong, Andrew
    Wright, Alan F
    Zhang, Qunyuan
    Brennan, Eoin P
    Choi, Murim
    Dastani, Zari
    Drong, Alexander W
    Eriksson, Per
    Franco-Cereceda, Anders
    Gådin, Jesper R
    Gharavi, Ali G
    Goddard, Michael E
    Handsaker, Robert E
    Huang, Jinyan
    Karpe, Fredrik
    Kathiresan, Sekar
    Keildson, Sarah
    Kiryluk, Krzysztof
    Kubo, Michiaki
    Lee, Jong-Young
    Liang, Liming
    Lifton, Richard P
    Ma, Baoshan
    McCarroll, Steven A
    McKnight, Amy J
    Min, Josine L
    Moffatt, Miriam F
    Montgomery, Grant W
    Murabito, Joanne M
    Nicholson, George
    Nyholt, Dale R
    Okada, Yukinori
    Perry, John R B
    Dorajoo, Rajkumar
    Reinmaa, Eva
    Salem, Rany M
    Sandholm, Niina
    Scott, Robert A
    Stolk, Lisette
    Takahashi, Atsushi
    Tanaka, Toshihiro
    Van't Hooft, Ferdinand M
    Vinkhuyzen, Anna A E
    Westra, Harm-Jan
    Zheng, Wei
    Zondervan, Krina T
    Heath, Andrew C
    Arveiler, Dominique
    Bakker, Stephan J L
    Beilby, John
    Bergman, Richard N
    Blangero, John
    Bovet, Pascal
    Campbell, Harry
    Caulfield, Mark J
    Cesana, Giancarlo
    Chakravarti, Aravinda
    Chasman, Daniel I
    Chines, Peter S
    Collins, Francis S
    Crawford, Dana C
    Adrienne Cupples, L
    Cusi, Daniele
    Danesh, John
    de Faire, Ulf
    den Ruijter, Hester M
    Dominiczak, Anna F
    Erbel, Raimund
    Erdmann, Jeanette
    Eriksson, Johan G
    Farrall, Martin
    Felix, Stephan B
    Ferrannini, Ele
    Ferrières, Jean
    Ford, Ian
    Forouhi, Nita G
    Forrester, Terrence
    Franco, Oscar H
    Gansevoort, Ron T
    Gejman, Pablo V
    Gieger, Christian
    Gottesman, Omri
    Gudnason, Vilmundur
    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.
    Hall, Alistair S
    Harris, Tamara B
    Hattersley, Andrew T
    Hicks, Andrew A
    Hindorff, Lucia A
    Hingorani, Aroon D
    Hofman, Albert
    Homuth, Georg
    Kees Hovingh, G
    Humphries, Steve E
    Hunt, Steven C
    Hyppönen, Elina
    Illig, Thomas
    Jacobs, Kevin B
    Jarvelin, Marjo-Riitta
    Jöckel, Karl-Heinz
    Johansen, Berit
    Jousilahti, Pekka
    Wouter Jukema, J
    Jula, Antti M
    Kaprio, Jaakko
    Kastelein, John J P
    Keinanen-Kiukaanniemi, Sirkka M
    Kiemeney, Lambertus A
    Knekt, Paul
    Kooner, Jaspal S
    Kooperberg, Charles
    Kovacs, Peter
    Kraja, Aldi T
    Kumari, Meena
    Kuusisto, Johanna
    Lakka, Timo A
    Langenberg, Claudia
    Le Marchand, Loic
    Lehtimäki, Terho
    Lyssenko, Valeriya
    Männistö, Satu
    Marette, André
    Matise, Tara C
    McKenzie, Colin A
    McKnight, Barbara
    Moll, Frans L
    Morris, Andrew D
    Morris, Andrew P
    Murray, Jeffrey C
    Nelis, Mari
    Ohlsson, Claes
    Oldehinkel, Albertine J
    Ong, Ken K
    Madden, Pamela A F
    Pasterkamp, Gerard
    Peden, John F
    Peters, Annette
    Postma, Dirkje S
    Pramstaller, Peter P
    Price, Jackie F
    Qi, Lu
    Raitakari, Olli T
    Rankinen, Tuomo
    Rao, D C
    Rice, Treva K
    Ridker, Paul M
    Rioux, John D
    Ritchie, Marylyn D
    Rudan, Igor
    Salomaa, Veikko
    Samani, Nilesh J
    Saramies, Jouko
    Sarzynski, Mark A
    Schunkert, Heribert
    Schwarz, Peter E H
    Sever, Peter
    Shuldiner, Alan R
    Sinisalo, Juha
    Stolk, Ronald P
    Strauch, Konstantin
    Tönjes, Anke
    Trégouët, David-Alexandre
    Tremblay, Angelo
    Tremoli, Elena
    Virtamo, Jarmo
    Vohl, Marie-Claude
    Völker, Uwe
    Waeber, Gérard
    Willemsen, Gonneke
    Witteman, Jacqueline C
    Zillikens, M Carola
    Adair, Linda S
    Amouyel, Philippe
    Asselbergs, Folkert W
    Assimes, Themistocles L
    Bochud, Murielle
    Boehm, Bernhard O
    Boerwinkle, Eric
    Bornstein, Stefan R
    Bottinger, Erwin P
    Bouchard, Claude
    Cauchi, Stéphane
    Chambers, John C
    Chanock, Stephen J
    Cooper, Richard S
    de Bakker, Paul I W
    Dedoussis, George
    Ferrucci, Luigi
    Franks, Paul W
    Froguel, Philippe
    Groop, Leif C
    Haiman, Christopher A
    Hamsten, Anders
    Hui, Jennie
    Hunter, David J
    Hveem, Kristian
    Kaplan, Robert C
    Kivimaki, Mika
    Kuh, Diana
    Laakso, Markku
    Liu, Yongmei
    Martin, Nicholas G
    März, Winfried
    Melbye, Mads
    Metspalu, Andres
    Moebus, Susanne
    Munroe, Patricia B
    Njølstad, Inger
    Oostra, Ben A
    Palmer, Colin N A
    Pedersen, Nancy L
    Perola, Markus
    Pérusse, Louis
    Peters, Ulrike
    Power, Chris
    Quertermous, Thomas
    Rauramaa, Rainer
    Rivadeneira, Fernando
    Saaristo, Timo E
    Saleheen, Danish
    Sattar, Naveed
    Schadt, Eric E
    Schlessinger, David
    Eline Slagboom, P
    Snieder, Harold
    Spector, Tim D
    Thorsteinsdottir, Unnur
    Stumvoll, Michael
    Tuomilehto, Jaakko
    Uitterlinden, André G
    Uusitupa, Matti
    van der Harst, Pim
    Walker, Mark
    Wallaschofski, Henri
    Wareham, Nicholas J
    Watkins, Hugh
    Weir, David R
    Wichmann, H-Erich
    Wilson, James F
    Zanen, Pieter
    Borecki, Ingrid B
    Deloukas, Panos
    Fox, Caroline S
    Heid, Iris M
    O'Connell, Jeffrey R
    Strachan, David P
    Stefansson, Kari
    van Duijn, Cornelia M
    Abecasis, Gonçalo R
    Franke, Lude
    Frayling, Timothy M
    McCarthy, Mark I
    Visscher, Peter M
    Scherag, André
    Willer, Cristen J
    Boehnke, Michael
    Mohlke, Karen L
    Lindgren, Cecilia M
    Beckmann, Jacques S
    Barroso, Inês
    North, Kari E
    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.
    Hirschhorn, Joel N
    Loos, Ruth J F
    Speliotes, Elizabeth K
    Genetic studies of body mass index yield new insights for obesity biology2015In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 518, no 7538, p. 197-206Article in journal (Refereed)
    Abstract [en]

    Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10−8), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ~2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

  • 20. Lu, Yingchang
    et al.
    Day, Felix R
    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.
    Buchkovich, Martin L
    Na, Jianbo
    Bataille, Veronique
    Cousminer, Diana L
    Dastani, Zari
    Drong, Alexander W
    Esko, Tõnu
    Evans, David M
    Falchi, Mario
    Feitosa, Mary F
    Ferreira, Teresa
    Hedman, Åsa K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Haring, Robin
    Hysi, Pirro G
    Iles, Mark M
    Justice, Anne E
    Kanoni, Stavroula
    Lagou, Vasiliki
    Li, Rui
    Li, Xin
    Locke, Adam
    Lu, Chen
    Mägi, Reedik
    Perry, John R B
    Pers, Tune H
    Qi, Qibin
    Sanna, Marianna
    Schmidt, Ellen M
    Scott, William R
    Shungin, Dmitry
    Teumer, Alexander
    Vinkhuyzen, Anna A E
    Walker, Ryan W
    Westra, Harm-Jan
    Zhang, Mingfeng
    Zhang, Weihua
    Zhao, Jing Hua
    Zhu, Zhihong
    Afzal, Uzma
    Ahluwalia, Tarunveer Singh
    Bakker, Stephan J L
    Bellis, Claire
    Bonnefond, Amélie
    Borodulin, Katja
    Buchman, Aron S
    Cederholm, Tommy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Choh, Audrey C
    Choi, Hyung Jin
    Curran, Joanne E
    de Groot, Lisette C P G M
    De Jager, Philip L
    Dhonukshe-Rutten, Rosalie A M
    Enneman, Anke W
    Eury, Elodie
    Evans, Daniel S
    Forsen, Tom
    Friedrich, Nele
    Fumeron, Frédéric
    Garcia, Melissa E
    Gärtner, Simone
    Han, Bok-Ghee
    Havulinna, Aki S
    Hayward, Caroline
    Hernandez, Dena
    Hillege, Hans
    Ittermann, Till
    Kent, Jack W
    Kolcic, Ivana
    Laatikainen, Tiina
    Lahti, Jari
    Mateo Leach, Irene
    Lee, Christine G
    Lee, Jong-Young
    Liu, Tian
    Liu, Youfang
    Lobbens, Stéphane
    Loh, Marie
    Lyytikäinen, Leo-Pekka
    Medina-Gomez, Carolina
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Nalls, Mike A
    Nielson, Carrie M
    Oozageer, Laticia
    Pascoe, Laura
    Paternoster, Lavinia
    Polašek, Ozren
    Ripatti, Samuli
    Sarzynski, Mark A
    Shin, Chan Soo
    Narančić, Nina Smolej
    Spira, Dominik
    Srikanth, Priya
    Steinhagen-Thiessen, Elisabeth
    Sung, Yun Ju
    Swart, Karin M A
    Taittonen, Leena
    Tanaka, Toshiko
    Tikkanen, Emmi
    van der Velde, Nathalie
    van Schoor, Natasja M
    Verweij, Niek
    Wright, Alan F
    Yu, Lei
    Zmuda, Joseph M
    Eklund, Niina
    Forrester, Terrence
    Grarup, Niels
    Jackson, Anne U
    Kristiansson, Kati
    Kuulasmaa, Teemu
    Kuusisto, Johanna
    Lichtner, Peter
    Luan, Jian'an
    Mahajan, Anubha
    Männistö, Satu
    Palmer, Cameron D
    Ried, Janina S
    Scott, Robert A
    Stancáková, Alena
    Wagner, Peter J
    Demirkan, Ayse
    Döring, Angela
    Gudnason, Vilmundur
    Kiel, Douglas P
    Kühnel, Brigitte
    Mangino, Massimo
    Mcknight, Barbara
    Menni, Cristina
    O'Connell, Jeffrey R
    Oostra, Ben A
    Shuldiner, Alan R
    Song, Kijoung
    Vandenput, Liesbeth
    van Duijn, Cornelia M
    Vollenweider, Peter
    White, Charles C
    Boehnke, Michael
    Boettcher, Yvonne
    Cooper, Richard S
    Forouhi, Nita G
    Gieger, Christian
    Grallert, Harald
    Hingorani, Aroon
    Jørgensen, Torben
    Jousilahti, Pekka
    Kivimaki, Mika
    Kumari, Meena
    Laakso, Markku
    Langenberg, Claudia
    Linneberg, Allan
    Luke, Amy
    Mckenzie, Colin A
    Palotie, Aarno
    Pedersen, Oluf
    Peters, Annette
    Strauch, Konstantin
    Tayo, Bamidele O
    Wareham, Nicholas J
    Bennett, David A
    Bertram, Lars
    Blangero, John
    Blüher, Matthias
    Bouchard, Claude
    Campbell, Harry
    Cho, Nam H
    Cummings, Steven R
    Czerwinski, Stefan A
    Demuth, Ilja
    Eckardt, Rahel
    Eriksson, Johan G
    Ferrucci, Luigi
    Franco, Oscar H
    Froguel, Philippe
    Gansevoort, Ron T
    Hansen, Torben
    Harris, Tamara B
    Hastie, Nicholas
    Heliövaara, Markku
    Hofman, Albert
    Jordan, Joanne M
    Jula, Antti
    Kähönen, Mika
    Kajantie, Eero
    Knekt, Paul B
    Koskinen, Seppo
    Kovacs, Peter
    Lehtimäki, Terho
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Liu, Yongmei
    Orwoll, Eric S
    Osmond, Clive
    Perola, Markus
    Pérusse, Louis
    Raitakari, Olli T
    Rankinen, Tuomo
    Rao, D C
    Rice, Treva K
    Rivadeneira, Fernando
    Rudan, Igor
    Salomaa, Veikko
    Sørensen, Thorkild I A
    Stumvoll, Michael
    Tönjes, Anke
    Towne, Bradford
    Tranah, Gregory J
    Tremblay, Angelo
    Uitterlinden, André G
    van der Harst, Pim
    Vartiainen, Erkki
    Viikari, Jorma S
    Vitart, Veronique
    Vohl, Marie-Claude
    Völzke, Henry
    Walker, Mark
    Wallaschofski, Henri
    Wild, Sarah
    Wilson, James F
    Yengo, Loïc
    Bishop, D Timothy
    Borecki, Ingrid B
    Chambers, John C
    Cupples, L Adrienne
    Dehghan, Abbas
    Deloukas, Panos
    Fatemifar, Ghazaleh
    Fox, Caroline
    Furey, Terrence S
    Franke, Lude
    Han, Jiali
    Hunter, David J
    Karjalainen, Juha
    Karpe, Fredrik
    Kaplan, Robert C
    Kooner, Jaspal S
    McCarthy, Mark I
    Murabito, Joanne M
    Morris, Andrew P
    Bishop, Julia A N
    North, Kari E
    Ohlsson, Claes
    Ong, Ken K
    Prokopenko, Inga
    Richards, J Brent
    Schadt, Eric E
    Spector, Tim D
    Widén, Elisabeth
    Willer, Cristen J
    Yang, Jian
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Mohlke, Karen L
    Hirschhorn, Joel N
    Pospisilik, John Andrew
    Zillikens, M Carola
    Lindgren, Cecilia
    Kilpeläinen, Tuomas Oskari
    Loos, Ruth J F
    New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk2016In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, article id 10495Article in journal (Refereed)
    Abstract [en]

    To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.

  • 21.
    Mendelson, Michael M.
    et al.
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.;Boston Univ, Sch Med, Boston, MA 02118 USA.;Boston Childrens Hosp, Dept Cardiol, Boston, MA USA.;NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA..
    Marioni, Riccardo E.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9YL, Midlothian, Scotland.;Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Med Genet Sect, Edinburgh EH8 9YL, Midlothian, Scotland.;Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia..
    Joehanes, Roby
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.;NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA.;Harvard Med Sch, Hebrew SeniorLife, Boston, MA USA..
    Liu, Chunyu
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.;NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA.;Boston Univ, Dept Biostat, Boston, MA USA..
    Hedman, Åsa K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Aslibekyan, Stella
    Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA..
    Demerath, Ellen W.
    Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA..
    Guan, Weihua
    Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA..
    Zhi, Degui
    Univ Alabama Birmingham, Sch Publ Hlth, Dept Biostat, Birmingham, AL 35294 USA..
    Yao, Chen
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.;NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA..
    Huan, Tianxiao
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.;NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA..
    Willinger, Christine
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.;NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA..
    Chen, Brian
    NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA..
    Courchesne, Paul
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.;NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA..
    Multhaup, Michael
    Johns Hopkins Univ, Sch Med, Ctr Epigenet, Baltimore, MD USA..
    Lrvin, Marguerite R.
    Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA..
    Cohain, Ariella
    Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA..
    Schadt, Eric E.
    Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA..
    Grove, Megan L.
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA..
    Bressler, Jan
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA..
    North, Kari
    Univ North Carolina Chapel Hill, Dept Epidemiol, Chapel Hill, NC USA..
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Gustafsson, Stefan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Shah, Sonia
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia.;Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    McRae, Allan F.
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia.;Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Harris, Sarah E.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9YL, Midlothian, Scotland.;Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Med Genet Sect, Edinburgh EH8 9YL, Midlothian, Scotland..
    Gibson, Jude
    Univ Edinburgh, Western Gen Hosp, Wellcome Trust Clin Res Facil, Edinburgh EH8 9YL, Midlothian, Scotland..
    Redmond, Paul
    Univ Edinburgh, Dept Psychol, Edinburgh EH8 9YL, Midlothian, Scotland..
    Coriey, Janie
    Univ Edinburgh, Dept Psychol, Edinburgh EH8 9YL, Midlothian, Scotland..
    Murphy, Lee
    Univ Edinburgh, Western Gen Hosp, Wellcome Trust Clin Res Facil, Edinburgh EH8 9YL, Midlothian, Scotland..
    Starr, John M.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9YL, Midlothian, Scotland.;Univ Edinburgh, Alzheimer Scotland Dementia Res Ctr, Edinburgh EH8 9YL, Midlothian, Scotland..
    Kleinbrink, Erica
    Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA.;Wayne State Univ, Dept Neurol, Detroit, MI USA..
    Lipovich, Leonard
    Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA.;Wayne State Univ, Dept Neurol, Detroit, MI USA..
    Visscher, Peter M.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9YL, Midlothian, Scotland.;Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia.;Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Wray, Naomi R.
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia.;Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Krauss, Ronald M.
    Childrens Hosp Oakland Res Inst, Oakland, CA USA..
    Fallin, Daniele
    Johns Hopkins Univ, Sch Med, Ctr Epigenet, Baltimore, MD USA..
    Feinberg, Andrew
    Johns Hopkins Univ, Sch Med, Ctr Epigenet, Baltimore, MD USA..
    Absher, Devin M.
    HudsonAlpha Inst Biotechnol, Huntsville, AL USA..
    Fornage, Myriam
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA.;Univ Texas Houston, Brown Fdn Inst Mol Med, Houston, TX USA..
    Pankow, James S.
    Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA..
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Fox, Caroline
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.;NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 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..
    Arnett, Donna K.
    Univ Kentucky, Coll Publ Hlth, Lexington, KY USA..
    Boerwinkle, Eric
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA.;Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA..
    Liang, Liming
    Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.;Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA..
    Levy, Daniel
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.;NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA..
    Deary, Lan J.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9YL, Midlothian, Scotland.;Univ Edinburgh, Dept Psychol, Edinburgh EH8 9YL, Midlothian, Scotland..
    Association of Body Mass Index with DNA Methylation and Gene Expression in Blood Cells and Relations to Cardiometabolic Disease: A Mendelian Randomization Approach2017In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 14, no 1, article id e1002215Article in journal (Refereed)
    Abstract [en]

    Background The link between DNA methylation, obesity, and adiposity-related diseases in the general population remains uncertain. Methods and Findings We conducted an association study of body mass index (BMI) and differential methylation for over 400,000 CpGs assayed by microarray in whole-blood-derived DNA from 3,743 participants in the Framingham Heart Study and the Lothian Birth Cohorts, with independent replication in three external cohorts of 4,055 participants. We examined variations in whole blood gene expression and conducted Mendelian randomization analyses to investigate the functional and clinical relevance of the findings. We identified novel and previously reported BMI-related differential methylation at 83 CpGs that replicated across cohorts; BMI-related differential methylation was associated with concurrent changes in the expression of genes in lipid metabolism pathways. Genetic instrumental variable analysis of alterations in methylation at one of the 83 replicated CpGs, cg11024682 (intronic to sterol regulatory element binding transcription factor 1 [SREBF1]), demonstrated links to BMI, adiposity-related traits, and coronary artery disease. Independent genetic instruments for expression of SREBF1 supported the findings linking methylation to adiposity and cardiometabolic disease. Methylation at a substantial proportion (16 of 83) of the identified loci was found to be secondary to differences in BMI. However, the cross-sectional nature of the data limits definitive causal determination. Conclusions We present robust associations of BMI with differential DNA methylation at numerous loci in blood cells. BMI-related DNA methylation and gene expression provide mechanistic insights into the relationship between DNA methylation, obesity, and adiposity-related diseases.

  • 22. 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.

  • 23. 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.

  • 24. Pfeiffer, L.
    et al.
    Wahl, S.
    Pilling, L. C.
    Reischl, E.
    Sandling, J. K.
    Kunze, S.
    Holdt, L. M.
    Kretschmer, A.
    Schramm, K.
    Adamski, J.
    Klopp, N.
    Illig, T.
    Hedman, A. K.
    Roden, M.
    Hernandez, D. G.
    Singleton, A. B.
    Thasler, W. E.
    Grallert, H.
    Gieger, C.
    Herder, C.
    Teupser, D.
    Meisinger, C.
    Spector, T. D.
    Kronenberg, F.
    Prokisch, H.
    Melzer, D.
    Peters, A.
    Deloukas, P.
    Ferrucci, L.
    Waldenberger, M.
    DNA methylation of lipid-related genes affects blood lipid levels2015In: Circ Cardiovasc Genet, Vol. 8, no 2, p. 334-42Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Epigenetic mechanisms might be involved in the regulation of interindividual lipid level variability and thus may contribute to the cardiovascular risk profile. The aim of this study was to investigate the association between genome-wide DNA methylation and blood lipid levels high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, and total cholesterol. Observed DNA methylation changes were also further analyzed to examine their relationship with previous hospitalized myocardial infarction. METHODS AND RESULTS: Genome-wide DNA methylation patterns were determined in whole blood samples of 1776 subjects of the Cooperative Health Research in the Region of Augsburg F4 cohort using the Infinium HumanMethylation450 BeadChip (Illumina). Ten novel lipid-related CpG sites annotated to various genes including ABCG1, MIR33B/SREBF1, and TNIP1 were identified. CpG cg06500161, located in ABCG1, was associated in opposite directions with both high-density lipoprotein cholesterol (beta coefficient=-0.049; P=8.26E-17) and triglyceride levels (beta=0.070; P=1.21E-27). Eight associations were confirmed by replication in the Cooperative Health Research in the Region of Augsburg F3 study (n=499) and in the Invecchiare in Chianti, Aging in the Chianti Area study (n=472). Associations between triglyceride levels and SREBF1 and ABCG1 were also found in adipose tissue of the Multiple Tissue Human Expression Resource cohort (n=634). Expression analysis revealed an association between ABCG1 methylation and lipid levels that might be partly mediated by ABCG1 expression. DNA methylation of ABCG1 might also play a role in previous hospitalized myocardial infarction (odds ratio, 1.15; 95% confidence interval=1.06-1.25). CONCLUSIONS: Epigenetic modifications of the newly identified loci might regulate disturbed blood lipid levels and thus contribute to the development of complex lipid-related diseases.

  • 25. Price, Thomas S
    et al.
    Regan, Regina
    Mott, Richard
    Hedman, Åsa
    Honey, Ben
    Daniels, Rachael J
    Smith, Lee
    Greenfield, Andy
    Tiganescu, Ana
    Buckle, Veronica
    Ventress, Nicki
    Ayyub, Helena
    Salhan, Anita
    Pedraza-Diaz, Susana
    Broxholme, John
    Ragoussis, Jiannis
    Higgs, Douglas R
    Flint, Jonathan
    Knight, Samantha J L
    SW-ARRAY: a dynamic programming solution for the identification of copy-number changes in genomic DNA using array comparative genome hybridization data.2005In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 33, no 11Article in journal (Refereed)
    Abstract [en]

    Comparative genome hybridization (CGH) to DNA microarrays (array CGH) is a technique capable of detecting deletions and duplications in genomes at high resolution. However, array CGH studies of the human genome noting false negative and false positive results using large insert clones as probes have raised important concerns regarding the suitability of this approach for clinical diagnostic applications. Here, we adapt the Smith-Waterman dynamic-programming algorithm to provide a sensitive and robust analytic approach (SW-ARRAY) for detecting copy-number changes in array CGH data. In a blind series of hybridizations to arrays consisting of the entire tiling path for the terminal 2 Mb of human chromosome 16p, the method identified all monosomies between 267 and 1567 kb with a high degree of statistical significance and accurately located the boundaries of deletions in the range 267-1052 kb. The approach is unique in offering both a nonparametric segmentation procedure and a nonparametric test of significance. It is scalable and well-suited to high resolution whole genome array CGH studies that use array probes derived from large insert clones as well as PCR products and oligonucleotides.

  • 26. Rahmioglu, Nilufer
    et al.
    Macgregor, Stuart
    Drong, Alexander W.
    Hedman, Åsa K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Harris, Holly R.
    Randall, Joshua C.
    Prokopenko, Inga
    Nyholt, Dale R.
    Morris, Andrew P.
    Montgomery, Grant W.
    Missmer, Stacey A.
    Lindgren, Cecilia M.
    Zondervan, Krina T.
    Genome-wide enrichment analysis between endometriosis and obesity-related traits reveals novel susceptibility loci2015In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 24, no 4, p. 1185-1199Article in journal (Refereed)
    Abstract [en]

    Endometriosis is a chronic inflammatory condition in women that results in pelvic pain and subfertility, and has been associated with decreased body mass index (BMI). Genetic variants contributing to the heritable component have started to emerge from genome-wide association studies (GWAS), although the majority remain unknown. Unexpectedly, we observed an intergenic locus on 7p15.2 that was genome-wide significantly associated with both endometriosis and fat distribution (waist-to-hip ratio adjusted for BMI; WHRadjBMI) in an independent meta-GWAS of European ancestry individuals. This led us to investigate the potential overlap in genetic variants underlying the aetiology of endometriosis, WHRadjBMI and BMI using GWAS data. Our analyses demonstrated significant enrichment of common variants between fat distribution and endometriosis (P = 3.7 x 10(-3)), which was stronger when we restricted the investigation to more severe (Stage B) cases (P = 4.5 x 10(-4)). However, no genetic enrichment was observed between endometriosis and BMI (P = 0.79). In addition to 7p15.2, we identify four more variants with statistically significant evidence of involvement in both endometriosis and WHRadjBMI (in/near KIFAP3, CAB39L, WNT4, GRB14); two of these, KIFAP3 and CAB39L, are novel associations for both traits. KIFAP3, WNT4 and 7p15.2 are associated with the WNT signalling pathway; formal pathway analysis confirmed a statistically significant (P = 6.41 x 10(-4)) overrepresentation of shared associations in developmental processes/WNT signalling between the two traits. Our results demonstrate an example of potential biological pleiotropy that was hitherto unknown, and represent an opportunity for functional follow-up of loci and further cross-phenotype comparisons to assess how fat distribution and endometriosis pathogenesis research fields can inform each other.

  • 27. Shungin, Dmitry
    et al.
    Winkler, Thomas W
    Croteau-Chonka, Damien C
    Ferreira, Teresa
    Locke, Adam E
    Mägi, Reedik
    Strawbridge, Rona J
    Pers, Tune H
    Fischer, Krista
    Justice, Anne E
    Workalemahu, Tsegaselassie
    Wu, Joseph M W
    Buchkovich, Martin L
    Heard-Costa, Nancy L
    Roman, Tamara S
    Drong, Alexander W
    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.
    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.
    Day, Felix R
    Esko, Tonu
    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.
    Kutalik, Zoltán
    Luan, Jian'an
    Randall, Joshua C
    Scherag, André
    Vedantam, Sailaja
    Wood, Andrew R
    Chen, Jin
    Fehrmann, Rudolf
    Karjalainen, Juha
    Kahali, Bratati
    Liu, Ching-Ti
    Schmidt, Ellen M
    Absher, Devin
    Amin, Najaf
    Anderson, Denise
    Beekman, Marian
    Bragg-Gresham, Jennifer L
    Buyske, Steven
    Demirkan, Ayse
    Ehret, Georg B
    Feitosa, Mary F
    Goel, Anuj
    Jackson, Anne U
    Johnson, Toby
    Kleber, Marcus E
    Kristiansson, Kati
    Mangino, Massimo
    Mateo Leach, Irene
    Medina-Gomez, Carolina
    Palmer, Cameron D
    Pasko, Dorota
    Pechlivanis, Sonali
    Peters, Marjolein J
    Prokopenko, Inga
    Stančáková, Alena
    Ju Sung, Yun
    Tanaka, Toshiko
    Teumer, Alexander
    Van Vliet-Ostaptchouk, Jana V
    Yengo, Loïc
    Zhang, Weihua
    Albrecht, Eva
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Arscott, Gillian M
    Bandinelli, Stefania
    Barrett, Amy
    Bellis, Claire
    Bennett, Amanda J
    Berne, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Blüher, Matthias
    Böhringer, Stefan
    Bonnet, Fabrice
    Böttcher, Yvonne
    Bruinenberg, Marcel
    Carba, Delia B
    Caspersen, Ida H
    Clarke, Robert
    Daw, E Warwick
    Deelen, Joris
    Deelman, Ewa
    Delgado, Graciela
    Doney, Alex S F
    Eklund, Niina
    Erdos, Michael R
    Estrada, Karol
    Eury, Elodie
    Friedrich, Nele
    Garcia, Melissa E
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Gigante, Bruna
    Go, Alan S
    Golay, Alain
    Grallert, Harald
    Grammer, Tanja B
    Gräßler, Jürgen
    Grewal, Jagvir
    Groves, Christopher J
    Haller, Toomas
    Hallmans, Goran
    Hartman, Catharina A
    Hassinen, Maija
    Hayward, Caroline
    Heikkilä, Kauko
    Herzig, Karl-Heinz
    Helmer, Quinta
    Hillege, Hans L
    Holmen, Oddgeir
    Hunt, Steven C
    Isaacs, Aaron
    Ittermann, Till
    James, Alan L
    Johansson, Ingegerd
    Juliusdottir, Thorhildur
    Kalafati, Ioanna-Panagiota
    Kinnunen, Leena
    Koenig, Wolfgang
    Kooner, Ishminder K
    Kratzer, Wolfgang
    Lamina, Claudia
    Leander, Karin
    Lee, Nanette R
    Lichtner, Peter
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Lindström, Jaana
    Lobbens, Stéphane
    Lorentzon, Mattias
    Mach, François
    Magnusson, Patrik K E
    Mahajan, Anubha
    McArdle, Wendy L
    Menni, Cristina
    Merger, Sigrun
    Mihailov, Evelin
    Milani, Lili
    Mills, Rebecca
    Moayyeri, Alireza
    Monda, Keri L
    Mooijaart, Simon P
    Mühleisen, Thomas W
    Mulas, Antonella
    Müller, Gabriele
    Müller-Nurasyid, Martina
    Nagaraja, Ramaiah
    Nalls, Michael A
    Narisu, Narisu
    Glorioso, Nicola
    Nolte, Ilja M
    Olden, Matthias
    Rayner, Nigel W
    Renstrom, Frida
    Ried, Janina S
    Robertson, Neil R
    Rose, Lynda M
    Sanna, Serena
    Scharnagl, Hubert
    Scholtens, Salome
    Sennblad, Bengt
    Seufferlein, Thomas
    Sitlani, Colleen M
    Vernon Smith, Albert
    Stirrups, Kathleen
    Stringham, Heather M
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Swertz, Morris A
    Swift, Amy J
    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.
    Tayo, Bamidele O
    Thorand, Barbara
    Thorleifsson, Gudmar
    Tomaschitz, Andreas
    Troffa, Chiara
    van Oort, Floor V A
    Verweij, Niek
    Vonk, Judith M
    Waite, Lindsay L
    Wennauer, Roman
    Wilsgaard, Tom
    Wojczynski, Mary K
    Wong, Andrew
    Zhang, Qunyuan
    Hua Zhao, Jing
    Brennan, Eoin P
    Choi, Murim
    Eriksson, Per
    Folkersen, Lasse
    Franco-Cereceda, Anders
    Gharavi, Ali G
    Hedman, Åsa K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hivert, Marie-France
    Huang, Jinyan
    Kanoni, Stavroula
    Karpe, Fredrik
    Keildson, Sarah
    Kiryluk, Krzysztof
    Liang, Liming
    Lifton, Richard P
    Ma, Baoshan
    McKnight, Amy J
    McPherson, Ruth
    Metspalu, Andres
    Min, Josine L
    Moffatt, Miriam F
    Montgomery, Grant W
    Murabito, Joanne M
    Nicholson, George
    Nyholt, Dale R
    Olsson, Christian
    Perry, John R B
    Reinmaa, Eva
    Salem, Rany M
    Sandholm, Niina
    Schadt, Eric E
    Scott, Robert A
    Stolk, Lisette
    Vallejo, Edgar E
    Westra, Harm-Jan
    Zondervan, Krina T
    Amouyel, Philippe
    Arveiler, Dominique
    Bakker, Stephan J L
    Beilby, John
    Bergman, Richard N
    Blangero, John
    Brown, Morris J
    Burnier, Michel
    Campbell, Harry
    Chakravarti, Aravinda
    Chines, Peter S
    Claudi-Boehm, Simone
    Collins, Francis S
    Crawford, Dana C
    Danesh, John
    de Faire, Ulf
    de Geus, Eco J C
    Dörr, Marcus
    Erbel, Raimund
    Eriksson, Johan G
    Farrall, Martin
    Ferrannini, Ele
    Ferrières, Jean
    Forouhi, Nita G
    Forrester, Terrence
    Franco, Oscar H
    Gansevoort, Ron T
    Gieger, Christian
    Gudnason, Vilmundur
    Haiman, Christopher A
    Harris, Tamara B
    Hattersley, Andrew T
    Heliövaara, Markku
    Hicks, Andrew A
    Hingorani, Aroon D
    Hoffmann, Wolfgang
    Hofman, Albert
    Homuth, Georg
    Humphries, Steve E
    Hyppönen, Elina
    Illig, Thomas
    Jarvelin, Marjo-Riitta
    Johansen, Berit
    Jousilahti, Pekka
    Jula, Antti M
    Kaprio, Jaakko
    Kee, Frank
    Keinanen-Kiukaanniemi, Sirkka M
    Kooner, Jaspal S
    Kooperberg, Charles
    Kovacs, Peter
    Kraja, Aldi T
    Kumari, Meena
    Kuulasmaa, Kari
    Kuusisto, Johanna
    Lakka, Timo A
    Langenberg, Claudia
    Le Marchand, Loic
    Lehtimäki, Terho
    Lyssenko, Valeriya
    Männistö, Satu
    Marette, André
    Matise, Tara C
    McKenzie, Colin A
    McKnight, Barbara
    Musk, Arthur W
    Möhlenkamp, Stefan
    Morris, Andrew D
    Nelis, Mari
    Ohlsson, Claes
    Oldehinkel, Albertine J
    Ong, Ken K
    Palmer, Lyle J
    Penninx, Brenda W
    Peters, Annette
    Pramstaller, Peter P
    Raitakari, Olli T
    Rankinen, Tuomo
    Rao, D C
    Rice, Treva K
    Ridker, Paul M
    Ritchie, Marylyn D
    Rudan, Igor
    Salomaa, Veikko
    Samani, Nilesh J
    Saramies, Jouko
    Sarzynski, Mark A
    Schwarz, Peter E H
    Shuldiner, Alan R
    Staessen, Jan A
    Steinthorsdottir, Valgerdur
    Stolk, Ronald P
    Strauch, Konstantin
    Tönjes, Anke
    Tremblay, Angelo
    Tremoli, Elena
    Vohl, Marie-Claude
    Völker, Uwe
    Vollenweider, Peter
    Wilson, James F
    Witteman, Jacqueline C
    Adair, Linda S
    Bochud, Murielle
    Boehm, Bernhard O
    Bornstein, Stefan R
    Bouchard, Claude
    Cauchi, Stéphane
    Caulfield, Mark J
    Chambers, John C
    Chasman, Daniel I
    Cooper, Richard S
    Dedoussis, George
    Ferrucci, Luigi
    Froguel, Philippe
    Grabe, Hans-Jörgen
    Hamsten, Anders
    Hui, Jennie
    Hveem, Kristian
    Jöckel, Karl-Heinz
    Kivimaki, Mika
    Kuh, Diana
    Laakso, Markku
    Liu, Yongmei
    März, Winfried
    Munroe, Patricia B
    Njølstad, Inger
    Oostra, Ben A
    Palmer, Colin N A
    Pedersen, Nancy L
    Perola, Markus
    Pérusse, Louis
    Peters, Ulrike
    Power, Chris
    Quertermous, Thomas
    Rauramaa, Rainer
    Rivadeneira, Fernando
    Saaristo, Timo E
    Saleheen, Danish
    Sinisalo, Juha
    Slagboom, P Eline
    Snieder, Harold
    Spector, Tim D
    Thorsteinsdottir, Unnur
    Stumvoll, Michael
    Tuomilehto, Jaakko
    Uitterlinden, André G
    Uusitupa, Matti
    van der Harst, Pim
    Veronesi, Giovanni
    Walker, Mark
    Wareham, Nicholas J
    Watkins, Hugh
    Wichmann, H-Erich
    Abecasis, Goncalo R
    Assimes, Themistocles L
    Berndt, Sonja I
    Boehnke, Michael
    Borecki, Ingrid B
    Deloukas, Panos
    Franke, Lude
    Frayling, Timothy M
    Groop, Leif C
    Hunter, David J
    Kaplan, Robert C
    O'Connell, Jeffrey R
    Qi, Lu
    Schlessinger, David
    Strachan, David P
    Stefansson, Kari
    van Duijn, Cornelia M
    Willer, Cristen J
    Visscher, Peter M
    Yang, Jian
    Hirschhorn, Joel N
    Zillikens, M Carola
    McCarthy, Mark I
    Speliotes, Elizabeth K
    North, Kari E
    Fox, Caroline S
    Barroso, Inês
    Franks, Paul W
    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.
    Heid, Iris M
    Loos, Ruth J F
    Cupples, L Adrienne
    Morris, Andrew P
    Lindgren, Cecilia M
    Mohlke, Karen L
    New genetic loci link adipose and insulin biology to body fat distribution2015In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 518, no 7538, p. 187-196Article in journal (Refereed)
    Abstract [en]

    Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

  • 28. Small, K. S.
    et al.
    Hedman, Åsa K.
    Grundberg, E.
    Nica, A. C.
    Thorleifsson, G.
    Kong, A.
    Thorsteindottir, U.
    Shin, S. Y.
    Richards, H. B.
    Soranzo, N.
    Ahmadi, K. R.
    Lindgren, C. M.
    Stefansson, K.
    Dermitzakis, E. T.
    Deloukas, P.
    Spector, T. D.
    McCarthy, M. I.
    Identification of an imprinted master trans regulator at the KLF14 locus related to multiple metabolic phenotypes2011In: Nat Genet, Vol. 43, no 6, p. 561-4Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies have identified many genetic variants associated with complex traits. However, at only a minority of loci have the molecular mechanisms mediating these associations been characterized. In parallel, whereas cis regulatory patterns of gene expression have been extensively explored, the identification of trans regulatory effects in humans has attracted less attention. Here we show that the type 2 diabetes and high-density lipoprotein cholesterol-associated cis-acting expression quantitative trait locus (eQTL) of the maternally expressed transcription factor KLF14 acts as a master trans regulator of adipose gene expression. Expression levels of genes regulated by this trans-eQTL are highly correlated with concurrently measured metabolic traits, and a subset of the trans-regulated genes harbor variants directly associated with metabolic phenotypes. This trans-eQTL network provides a mechanistic understanding of the effect of the KLF14 locus on metabolic disease risk and offers a potential model for other complex traits.

  • 29.
    Wang, Yunzhang
    et al.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Nobels Vag 12A, S-17177 Stockholm, Sweden.
    Karlsson, Robert
    Karolinska Inst, Dept Med Epidemiol & Biostat, Nobels Vag 12A, S-17177 Stockholm, Sweden.
    Lampa, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Zhang, Qian
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia.
    Hedman, Åsa K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden.
    Almgren, Malin
    Karolinska Inst, Ctr Mol Med, Dept Clin Neurosci, Stockholm, Sweden.
    Almqvist, Catarina
    Karolinska Inst, Dept Med Epidemiol & Biostat, Nobels Vag 12A, S-17177 Stockholm, Sweden;Karolinska Univ Hosp, Astrid Lindgren Childrens Hosp, Stockholm, Sweden.
    McRae, Allan F.
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia.
    Marioni, Riccardo E.
    Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Edinburgh, Midlothian, Scotland;Univ Edinburgh, Dept Psychol, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland.
    Ingelsson, Erik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Stanford Univ, Sch Med, Div Cardiovasc Med, Dept Med, Stanford, CA 94305 USA;Stanford Univ, Stanford Cardiovasc Inst, Stanford, CA 94305 USA.
    Visscher, Peter M.
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia;Univ Queensland, Queensland Brain Inst, St Lucia, Qld, Australia.
    Deary, Ian J.
    Univ Edinburgh, Dept Psychol, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Morris, Tiffany
    UCL, Canc Inst, London, England.
    Beck, Stephan
    UCL, Canc Inst, London, England.
    Pedersen, Nancy L.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Nobels Vag 12A, S-17177 Stockholm, Sweden.
    Hagg, Sara
    Karolinska Inst, Dept Med Epidemiol & Biostat, Nobels Vag 12A, S-17177 Stockholm, Sweden.
    Epigenetic influences on aging: a longitudinal genome-wide methylation study in old Swedish twins2018In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 13, no 9, p. 975-987Article in journal (Refereed)
    Abstract [en]

    Age-related changes in DNA methylation were observed in cross-sectional studies, but longitudinal evidence is still limited. Here, we aimed to characterize longitudinal age-related methylation patterns using 1011 blood samples collected from 385 Swedish twins (age at entry: mean 69 and standard deviation 9.7, 73 monozygotic and 96 dizygotic pairs) up to five times (mean 2.6) over 20 years (mean 8.7). We identified 1316 age-associated methylation sites (P<1.3x10(-7)) using a longitudinal epigenome-wide association study design. We measured how estimated cellular compositions changed with age and how much they confounded the age effect. We validated the results in two independent longitudinal cohorts, where 118 CpGs were replicated in Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS, 390 samples) (P<3.9x10(-5)), 594 in Lothian Birth Cohort (LBC, 3018 samples) (P<5.1x10(-5)) and 63 in both. Functional annotation of age-associated CpGs showed enrichment in CCCTC-binding factor (CTCF) and other transcription factor binding sites. We further investigated genetic influences on methylation and found no interaction between age and genetic effects in the 1316 age-associated CpGs. Moreover, in the same CpGs, methylation differences within twin pairs increased with 6.4% over 10 years, where monozygotic twins had smaller intra-pair differences than dizygotic twins. In conclusion, we show that age-related methylation changes persist in a longitudinal perspective, and are fairly stable across cohorts. The changes are under genetic influence, although this effect is independent of age. Moreover, methylation variability increase over time, especially in age-associated CpGs, indicating the increase of environmental contributions on DNA methylation with age.

  • 30. 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.

1 - 30 of 30
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf