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

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

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  • 2.
    Berghoff, Bork A.
    et al.
    Justus Liebig Univ, Inst Mikrobiol & Mol Biol, Giessen, Germany..
    Karlsson, Torgny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Kallman, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wagner, Gerhart E. H.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Grabherr, Manfred G.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    RNA-sequence data normalization through in silico prediction of reference genes: the bacterial response to DNA damage as case study2017In: BioData Mining, E-ISSN 1756-0381, Vol. 10, article id 30Article in journal (Refereed)
    Abstract [en]

    Background: Measuring how gene expression changes in the course of an experiment assesses how an organism responds on a molecular level. Sequencing of RNA molecules, and their subsequent quantification, aims to assess global gene expression changes on the RNA level (transcriptome). While advances in high-throughput RNA-sequencing (RNA-seq) technologies allow for inexpensive data generation, accurate post-processing and normalization across samples is required to eliminate any systematic noise introduced by the biochemical and/or technical processes. Existing methods thus either normalize on selected known reference genes that are invariant in expression across the experiment, assume that the majority of genes are invariant, or that the effects of up-and down-regulated genes cancel each other out during the normalization.

    Results: Here, we present a novel method, moose(2), which predicts invariant genes in silico through a dynamic programming (DP) scheme and applies a quadratic normalization based on this subset. The method allows for specifying a set of known or experimentally validated invariant genes, which guides the DP. We experimentally verified the predictions of this method in the bacterium Escherichia coli, and show how moose(2) is able to (i) estimate the expression value distances between RNA-seq samples, (ii) reduce the variation of expression values across all samples, and (iii) to subsequently reveal new functional groups of genes during the late stages of DNA damage. We further applied the method to three eukaryotic data sets, on which its performance compares favourably to other methods. The software is implemented in C++ and is publicly available from http://grabherr.github.io/moose2/.

    Conclusions: The proposed RNA-seq normalization method, moose(2), is a valuable alternative to existing methods, with two major advantages: (i) in silico prediction of invariant genes provides a list of potential reference genes for downstream analyses, and (ii) non-linear artefacts in RNA-seq data are handled adequately to minimize variations between replicates.

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  • 3.
    Clark, David W.
    et al.
    Univ Edinburgh, Usher Inst, Ctr Global Hlth Res, Edinburgh, Midlothian, Scotland.
    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.
    Sennblad, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Ctr Mol Med, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden.
    Gyllensten, Ulf B.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Johansson, Åsa
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Wilson, James F.
    Univ Edinburgh, Usher Inst, Ctr Global Hlth Res, Edinburgh, Midlothian, Scotland; Osaka Univ, Dept Stat Genet, Grad Sch Med, Suita, Osaka, Japan; Osaka Univ, Immunol Frontier Res Ctr WPI IFReC, Lab Stat Immunol, Suita, Osaka, Japan; Amgen Inc, DeCODE Genet, Reykjavik, Iceland.
    Associations of autozygosity with a broad range of human phenotypes2019In: Nature Communications, E-ISSN 2041-1723, Vol. 10, article id 4957Article in journal (Refereed)
    Abstract [en]

    In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F-ROH) for >1.4 million individuals, we show that F-ROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F-ROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F-ROH are confirmed within full-sibling pairs, where the variation in F-ROH is independent of all environmental confounding.

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  • 4.
    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.
    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.
    Hernándes, Carlos Azuaje
    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.
    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.
    Breast-feeding and risk of asthma, hay fever, and eczema2018In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 141, no 3, p. 1157-+Article in journal (Other academic)
  • 5.
    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.
    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.
    Höglund, Julia
    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.
    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.
    Causal effects of inflammatory protein biomarkers on inflammatory diseases2021In: Science Advances, E-ISSN 2375-2548, Vol. 7, no 50, article id eabl4359Article in journal (Refereed)
    Abstract [en]

    Many circulating proteins are associated with the presence or severity of disease. However, whether these protein biomarkers are causal for disease development is usually unknown. We investigated the causal effect of 21 well-known or exploratory protein biomarkers of inflammation on 18 inflammatory diseases using two-sample Mendelian randomization. We identified six proteins to have causal effects on any of 11 inflammatory diseases (FDR < 0.05, corresponding to P < 1.4 x 10(-3)). IL-12B protects against psoriasis and psoriatic arthropathy, LAP-TGF-beta-1 protects against osteoarthritis, TWEAK protects against asthma, VEGF-A protects against ulcerative colitis, and LT-alpha protects against both type 1 diabetes and rheumatoid arthritis. In contrast, IL-18R1 increases the risk of developing allergy, hay fever, and eczema. Most proteins showed protective effects against development of disease rather than increasing disease risk, which indicates that many disease-related biomarkers are expressed to protect from tissue damage. These proteins represent potential intervention points for disease prevention and treatment.

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  • 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.
    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.
    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.
    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.
    Gyllensten, Ulf B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Johansson, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Genetic variants influencing phenotypic variance heterogeneity2018In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 27, no 5, p. 799-810Article in journal (Refereed)
    Abstract [en]

    Most genetic studies identify genetic variants associated with disease risk or with the mean value of a quantitative trait. More rarely, genetic variants associated with variance heterogeneity are considered. In this study, we have identified such variance single-nucleotide polymorphisms (vSNPs) and examined if these represent biological gene x gene or gene x environment interactions or statistical artifacts caused by multiple linked genetic variants influencing the same phenotype. We have performed a genome-wide study, to identify vSNPs associated with variance heterogeneity in DNA methylation levels. Genotype data from over 10 million single-nucleotide polymorphisms (SNPs), and DNA methylation levels at over 430 000 CpG sites, were analyzed in 729 individuals. We identified vSNPs for 7195 CpG sites (P < 9.4 x 10(-11)). This is a relatively low number compared to 52 335 CpG sites for which SNPs were associated with mean DNA methylation levels. We further showed that variance heterogeneity between genotypes mainly represents additional, often rare, SNPs in linkage disequilibrium (LD) with the respective vSNP and for some vSNPs, multiple low frequency variants co-segregating with one of the vSNP alleles. Therefore, our results suggest that variance heterogeneity of DNA methylation mainly represents phenotypic effects by multiple SNPs, rather than biological interactions. Such effects may also be important for interpreting variance heterogeneity of more complex clinical phenotypes.

  • 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.
    Höglund, Julia
    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.
    Hadizadeh, Fatemeh
    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.
    Ek, Weronica E.
    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.
    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.
    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.
    Gene-based variant analysis of whole-exome sequencing in relation to eosinophil count2022In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 13, article id 862255Article in journal (Refereed)
    Abstract [en]

    Eosinophils play important roles in the release of cytokine mediators in response to inflammation. Many associations between common genetic variants and eosinophils have already been reported, using single nucleotide polymorphism (SNP) array data. Here, we have analyzed 200,000 whole-exome sequences (WES) from the UK Biobank cohort and performed gene-based analyses of eosinophil count. We defined five different variant weighting schemes to incorporate information on both deleteriousness and frequency. A total of 220 genes in 55 distinct (>10 Mb apart) genomic regions were found to be associated with eosinophil count, of which seven genes (ALOX15, CSF2RB, IL17RA, IL33, JAK2, S1PR4, and SH2B3) are driven by rare variants, independent of common variants identified in genome-wide association studies. Two additional genes, NPAT and RMI1, have not been associated with eosinophil count before and are considered novel eosinophil loci. These results increase our knowledge about the effect of rare variants on eosinophil count, which can be of great value for further identification of therapeutic targets.

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  • 9.
    Höglund, Julia
    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.
    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.
    Johansson, Therese
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, WoMHeR (Centre for Women’s Mental Health during the Reproductive Lifespan). Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ek, Weronica E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Johansson, Åsa
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Characterization of the human ABO genotypes and their association to common inflammatory and cardiovascular diseases in the UK Biobank2021In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 96, no 11, p. 1350-1362Article in journal (Refereed)
    Abstract [en]

    The ABO gene contains three major alleles that encodes different antigens; A, B, and O, which determine an individual's blood group. Previous studies have primarily focused on identifying associations between ABO blood groups and diseases risk. Here, we sought to test for association between ABO genotypes (OO, OA, AA; OB, BB, and AB) and a large set of common inflammatory and cardiovascular diseases in UK Biobank as well as disease-related protein biomarkers in NSPHS. We first tested for association by conducting a likelihood ratio test, testing whether ABO contributed significantly to the risk for 24 diseases, and 438 plasma proteins. For phenotypes with FDR < 0.05, we tested for pair-wise differences between genetically determined ABO genotypes using logistic or linear regression. Our study confirmed previous findings of a strong association between ABO and cardiovascular disease, identified associations for both type 1 and type 2 diabetes, and provide additional evidence of significant differences between heterozygous and homozygous allele carriers for pulmonary embolism, deep vein thrombosis, but also for von Willebrand factor levels. Furthermore, the results indicated an additive effect between genotypes, even between the two most common A subgroups, A1 and A2. Additionally, we found that ABO contributed significantly to 39 plasma proteins, of which 23 have never been linked to the ABO locus before. These results show the need of incorporating ABO genotype information in the consultation and management of patients at risk, rather than classifying patients into blood groups.

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  • 10.
    Höglund, Julia
    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.
    Rafati, Nima
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    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.
    Enroth, Stefan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    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.
    Ek, Weronica E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Johansson, Åsa
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Improved power and precision with whole genome sequencing data in genome-wide association studies of inflammatory biomarkers2019In: Scientific Reports, E-ISSN 2045-2322, Vol. 9, article id 16844Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies (GWAS) have identified associations between thousands of common genetic variants and human traits. However, common variants usually explain a limited fraction of the heritability of a trait. A powerful resource for identifying trait-associated variants is whole genome sequencing (WGS) data in cohorts comprised of families or individuals from a limited geographical area. To evaluate the power of WGS compared to imputations, we performed GWAS on WGS data for 72 inflammatory biomarkers, in a kinship-structured cohort. When using WGS data, we identified 18 novel associations that were not detected when analyzing the same biomarkers with genotyped or imputed SNPs. Five of the novel top variants were low frequency variants with a minor allele frequency (MAF) of <5%. Our results suggest that, even when applying a GWAS approach, we gain power and precision using WGS data, presumably due to more accurate determination of genotypes. The lack of a comparable dataset for replication of our results is a limitation in our study. However, this further highlights that there is a need for more genetic epidemiological studies based on WGS data.

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    FULLTEXT01
  • 11.
    Johansson, Therese
    et al.
    Uppsala University, WoMHeR (Centre for Women’s Mental Health during the Reproductive Lifespan). Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics and Neurobiology.
    Fowler, Philip
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Statistics.
    Ek, Weronica E.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics and Neurobiology.
    Skalkidou, Alkistis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Reproductive Health Research.
    Karlsson, Torgny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics and Neurobiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Johansson, Åsa
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics and Neurobiology.
    Oral Contraceptives, Hormone Replacement Therapy, and Stroke Risk2022In: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 53, no 10, p. 3107-3115Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Millions of women worldwide use exogenous hormones as oral contraceptives or hormone replacement therapy. Still, time-dependent and long-term consequences of exogenous hormones on stroke risk remains unclear.

    METHODS: We examined the association between self-reported oral contraceptive and hormone replacement therapy use and stroke risk in 257 194 women from the UK Biobank, born between 1939 and 1970. Outcomes included any type of stroke, ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage. Exposures were analyzed as time-varying variables in Cox regression models.

    RESULTS: During first year of oral contraceptive use, an increased event rate of any stroke was observed (hazard ratio [HR], 2.49 [95% CI, 1.44-4.30]), while the hazards were found to be comparable during remaining years of use (HR, 1.00 [95% CI, 0.86-1.14]), compared with nonusers. Similarly, first year of hormone replacement therapy use was associated with higher hazard rates of any stroke (HR, 2.12 [95% CI, 1.66-2.70]), as well as cause-specific stroke, including ischemic stroke (HR, 1.93 [95% CI, 1.05-3.57]) and subarachnoid hemorrhage (HR, 2.17 [95% CI, 1.25-3.78]), which remained increased for any stroke during remaining years of use (HR, 1.18 [95% CI, 1.05-1.31]), and after discontinuation (HR, 1.16 [95% CI, 1.02-1.32]).

    CONCLUSIONS: Oral contraceptive use and hormone replacement therapy were associated with an increased risk of stroke, especially during the first year of use, possibly due to immediate changes in hemostatic balance. This study provides new insights on the effects of hormone exposure on stroke risk and provide evidence of not only an overall risk but also a pronounced effects seen in the beginning of treatment.

  • 12.
    Johansson, Therese
    et al.
    Uppsala University, WoMHeR (Centre for Women’s Mental Health during the Reproductive Lifespan). Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics and Neurobiology.
    Vinther Larsen, S.
    Bui, M.
    Ek, Weronica E.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics and Neurobiology.
    Karlsson, Torgny
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics and Neurobiology.
    Johansson, Åsa
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics and Neurobiology.
    Population-based cohort study of oral contraceptive use and risk of depression2023In: Epidemiology and Psychiatric Sciences, ISSN 2045-7960, E-ISSN 2045-7979, Vol. 32, article id e39Article in journal (Refereed)
    Abstract [en]

    AIM: Research on the effect of oral contraceptive (OC) use on the risk of depression shows inconsistent findings, especially in adult OC users. One possible reason for this inconsistency is the omission of women who discontinue OCs due to adverse mood effects, leading to healthy user bias. To address this issue, we aim to estimate the risk of depression that is associated with the initiation of OCs as well as the effect of OC use on lifetime risk of depression.

    METHODS: This is a population-based cohort study based on data from 264,557 women from the UK Biobank. Incidence of depression was addressed via interviews, inpatient hospital or primary care data. The hazard ratio (HR) between OC use and incident depression was estimated by multivariable Cox regression with OC use as a time-varying exposure. To validate causality, we examined familial confounding in 7,354 sibling pairs.

    RESULTS: We observed that the first 2 years of OC use were associated with a higher rate of depression compared to never users (HR = 1.71, 95% confidence interval [CI]: 1.55-1.88). Although the risk was not as pronounced beyond the first 2 years, ever OC use was still associated with an increased lifetime risk of depression (HR = 1.05, 95% CI: 1.01-1.09). Previous OC use were associated with a higher rate of depression compared to never users, with adolescent OC users driving the increased hazard (HR = 1.18, 95% CI: 1.12-1.25). No significant association were observed among adult OC users who had previously used OCs (HR = 1.00, 95% CI: 0.95-1.04). Notably, the sibling analysis provided further evidence for a causal effect of OC use on the risk of depression.

    CONCLUSIONS: Our findings suggest that the use of OCs, particularly during the first 2 years, increases the risk of depression. Additionally, OC use during adolescence might increase the risk of depression later in life. Our results are consistent with a causal relationship between OC use and depression, as supported by the sibling analysis. This study highlights the importance of considering the healthy user bias as well as family-level confounding in studies of OC use and mental health outcomes. Physicians and patients should be aware of this potential risk when considering OCs, and individualized risk-benefit assessments should be conducted.

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  • 13.
    Johansson, Åsa
    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.
    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.
    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.
    Ek, Weronica E
    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 association analysis of 350 000 Caucasians from the UK Biobank identifies novel loci for asthma, hay fever and eczema2019In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 28, no 23, p. 4022-4041Article in journal (Refereed)
    Abstract [en]

    Even though heritability estimates suggest that the risk of asthma, hay fever and eczema is largely due to genetic factors, previous studies have not explained a large part of the genetics behind these diseases. In this GWA study, we include 346 545 Caucasians from the UK Biobank to identify novel loci for asthma, hay fever and eczema and replicate novel loci in three independent cohorts. We further investigate if associated lead SNPs have a significantly larger effect for one disease compared to the other diseases, to highlight possible disease specific effects. We identified 141 loci, of which 41 are novel, to be associated (P ≤ 3x10-8) with asthma, hay fever or eczema, analysed separately or as disease phenotypes that includes the presence of different combinations of these diseases. The largest number of loci were associated with the combined phenotype (asthma/hay fever/eczema). However, as many as 20 loci had a significantly larger effect on hay fever/eczema-only compared to their effects on asthma, while 26 loci exhibited larger effects on asthma compared with their effects on hay fever/eczema. At four of the novel loci, TNFRSF8, MYRF, TSPAN8, and BHMG1, the lead SNPs were in LD (> 0.8) with potentially casual missense variants. Our study shows that a large amount of the genetic contribution is shared between the diseases. Nonetheless, a number of SNPs have a significantly larger effect on one of the phenotypes suggesting that part of the genetic contribution is more phenotype specific.

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  • 14.
    Johansson, Åsa
    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.
    Schmitz, Daniel
    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.
    Höglund, Julia
    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.
    Hadizadeh, Fatemeh
    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.
    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.
    Ek, Weronica E.
    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.
    Investigating the Effect of Estradiol Levels on the Risk of Breast, Endometrial, and Ovarian Cancer2022In: Journal of the Endocrine Society, E-ISSN 2472-1972, Vol. 6, no 8, article id bvac100Article in journal (Refereed)
    Abstract [en]

    Background: High levels of estrogen are associated with increased risk of breast and endometrial cancer and have been suggested to also play a role in the development of ovarian cancer. Cancerogenic effects of estradiol, the most prominent form of estrogen, have been highlighted as a side effect of estrogen-only menopausal hormone therapy. However, whether high levels of endogenous estrogens, produced within the body, promote cancer development, has not been fully established.

    Objective: We aimed to examine causal effects of estradiol on breast, endometrial, and ovarian cancer.

    Methods: Here we performed a two-sample Mendelian randomization (MR) to estimate the effect of endogenous estradiol on the risk of developing breast, endometrial, and ovarian cancer, using the UK Biobank as well as 3 independent cancer cohorts.

    Results: Using 3 independent instrumental variables, we showed that higher estradiol levels significantly increase the risk for ovarian cancer (OR = 3.18 [95% CI, 1.47-6.87], P = 0.003). We also identified a nominally significant effect for ER-positive breast cancer (OR = 2.16 [95% CI, 1.09-4.26], P = 0.027). However, we could not establish a clear link to the risk of endometrial cancer (OR = 1.93 [95% CI, 0.77-4.80], P = 0.160).

    Conclusion: Our results suggest that high estradiol levels promote the development of ovarian and ER-positive breast cancer.

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  • 15.
    Karlsson, Torgny
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Theoretical Astrophysics.
    Bland-Hawthorn, J.
    Freeman, K. C.
    Silk, J.
    The chemical signature of a relic star cluster in the sextans dwarf spheroidal galaxy: Implications for near-field cosmology2012In: Astrophysical Journal, ISSN 0004-637X, E-ISSN 1538-4357, Vol. 759, no 2, p. 111-Article in journal (Refereed)
    Abstract [en]

    We present tentative evidence for the existence of a dissolved star cluster at [Fe/H] = -2.7 in the Sextans dwarf spheroidal galaxy. We use the technique of chemical tagging to identify stars that are highly clustered in a multi-dimensional chemical abundance space (-space). In a sample of six stars, three, possibly four, stars are identified as potential cluster stars. The initial stellar mass of the parent cluster is estimated from two independent observations to be , assuming a Salpeter (Kroupa) initial mass function. If corroborated by follow-up spectroscopy, this star cluster is the most metal-poor system identified to date. Chemical signatures of remnant clusters in dwarf galaxies like Sextans provide us with a very powerful probe to the high-redshift universe. From available observational data, we argue that the average star cluster mass in the majority of the newly discovered ultra-faint dwarf galaxies was notably lower than it is in the Galaxy today and possibly lower than in the more luminous, classical dwarf spheroidal galaxies. Furthermore, the mean cumulative metallicity function of the dwarf spheroidals falls below that of the ultra-faints, which increases with increasing metallicity as predicted from our stochastic chemical evolution model. These two findings, together with a possible difference in the 〈[Mg/Fe]〉 ratio suggest that the ultra-faint dwarf galaxy population, or a significant fraction thereof, and the dwarf spheroidal population were formed in different environments and would thus be distinct in origin.

  • 16.
    Karlsson, Torgny
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Theoretical Astrophysics.
    Bland-Hawthorn, Joss
    A Relic Star Cluster in the Sextans Dwarf Spheroidal Galaxy: Implications for Early Star and Galaxy Formation2012In: Conference on the Galactic Archaeology: Near-Field Cosmology and the Formation of the Milky Way, SAN FRANCISCO, 2012, Vol. 458, p. 257-260Conference paper (Other academic)
    Abstract [en]

    We present tentative evidence for the existence of a dissolved star cluster in the Sextans dwarf spheroidal galaxy. In a sample of six stars, we identify three (possibly four) stars around [Fe/H] = -2.7 that are highly clustered in a multi-dimensional chemical abundance space. The estimated initial stellar mass of the cluster is M-*,(init) = 1.9(-0.9)(+1.5) (1.6(-0.8)(+1.2)) x 10(5) M-circle dot assuming a Salpeter (Kroupa) initial mass function (IMF). If corroborated by follow-up spectroscopy, this ancient star cluster at [Fe/H] = -2.7 is the most metal-poor system identified to date. Inspired by this finding, we also present a new way to interpret the cumulative metallicity functions of dwarf galaxies. From available observational data, we speculate that the ultra-faint dwarf galaxy population, or a significant fraction thereof, and the more luminous, classical dwarf spheroidal population were formed in different environments and would thus be distinct in origin.

  • 17.
    Karlsson, Torgny
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Astronomy and Space Physics, Theoretical Astrophysics.
    Gustafsson, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Astronomy and Space Physics, Theoretical Astrophysics.
    Stochastic chemical enrichment in metal-poor systems II.: Abundance ratios and scatter2005In: Astronomy and Astrophysics, ISSN 0004-6361, E-ISSN 1432-0746, Vol. 436, no 6, p. 879-894Article in journal (Refereed)
    Abstract [en]

    A stochastic model of the chemical enrichment of metal-poor systems by core collapse supernovae is used to study the scatter in stellar abundance ratios. Large-scale mixing of the enriched material by turbulent motions and cloud collisions in the interstellar medium, and infall of pristine matter are taken into account. The resulting scatter in abundance ratios, e.g. as functions of the overall metallicity, is demonstrated to be crucially dependent on the as yet uncertain supernovae yields. The observed abundance ratios and their scatters therefore have diagnostic power as regards the yields. The relatively small star-to-star scatter observed in many chemical abundance ratios, e.g. by Cayrel et al. (2004) for stars down to [Fe/H]= -4, is tentatively explained by the averaging of a large number of contributing supernovae and by the cosmic selection effects favoring contributions from supernovae in a certain mass range for the most metal-poor stars. The scatter in observed abundances of -elements is understood in terms of observational errors only, while additional spread in yields or sites of nucleosynthesis may affect the odd-even elements Na and Al. For the iron-group elements we find some systematic deviations from observations in abundance ratios, such as systematically too high predicted Cr/Fe and Cr/Mg ratios, as well as differences between the different sets of yields, both in terms of predicted abundance ratios and scatter. The semi-empirical yields recently suggested by Francois et al. (2004) are found to lead to scatter in abundance ratios significantly greater than observed, when applied in the inhomogeneous models. "Spurs", very narrow sequences in abundance-ratio diagrams, may disclose a single-supernova origin of the elements of the stars on the sequence. Verification of the existence of such features, called single supernova sequences (SSSs), is challenging. This will require samples of several hundred stars with abundance ratios observed to accuracies of 0.05 dex or better.

  • 18.
    Karlsson, Torgny
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics and Neurobiology.
    Hadizadeh, Fatemeh
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics and Neurobiology.
    Rask-Andersen, Mathias
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics and Neurobiology.
    Johansson, Åsa
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics and Neurobiology.
    Ek, Weronica E.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics and Neurobiology.
    Body Mass Index and the Risk of Rheumatic Disease: Linear and Nonlinear Mendelian Randomization Analyses2023In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 75, no 11, p. 2027-2035Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: While the association between obesity and risk of rheumatic disease is well established, the precise causal relation has not been conclusively proved. Here, we estimate the causal effect of body mass index (BMI) on the risk of developing five different rheumatic diseases.

    METHODS: Linear and nonlinear mendelian randomization (MR) were used to estimate the effect of BMI on risk of rheumatic disease, and sex-specific effects were identified. Analyses were performed in 361,952 participants from the UK Biobank cohort for the five rheumatic diseases: rheumatoid arthritis (N=8,381 cases), osteoarthritis (N=87,430), psoriatic arthropathy (N=933), gout (N=13,638), and inflammatory spondylitis (N=4,328).

    RESULTS: Using linear MR, we found that one standard deviation higher BMI increases the incidence rate for rheumatoid arthritis (IRR=1.52; 95% CI=1.36-1.69), osteoarthritis (IRR=1.49; 1.43-1.55), psoriatic arthropathy (IRR=1.80; 1.31-2.48), gout (IRR=1.73; 1.56-1.92), and inflammatory spondylitis (IRR=1.34; 1.14-1.57) in all individuals. BMI was found to be a stronger risk factor in women compared to men for psoriatic arthropathy (sex-interaction P=3.3×10-4 ) and gout (P=4.3×10-3 ), and the effect on osteoarthritis was stronger in premenopausal compared to postmenopausal women (P=1.8×10-3 ). Nonlinear effects of BMI were identified for osteoarthritis and gout in men, and for gout in women. The nonlinearity for gout was also more extreme in men compared to women (P=0.03).

    CONCLUSION: Higher BMI causes an increased risk for rheumatic disease, an effect that is more pronounced in women for both gout and psoriatic arthropathy. The novel sex- and BMI-specific causal effects identified here, give further insight into rheumatic-disease etiology and mark an important step towards personalized medicine.

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  • 19.
    Karlsson, Torgny
    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.
    Johansson, Therese
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, WoMHeR (Centre for Women’s Mental Health during the Reproductive Lifespan).
    Höglund, Julia
    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.
    Ek, Weronica E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Johansson, Åsa
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Time-dependent effects of oral contraceptive use on breast, ovarian and endometrial cancers2021In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 81, no 4, p. 1153-1162Article in journal (Refereed)
    Abstract [en]

    Oral contraceptive use has been suggested to influence the risk of breast, ovarian, and endometrial cancer. The purpose of this study is to clarify the time-dependent effects between long-term oral contraceptive use and cancer risk. We performed an observational study in 256,661 women from UK Biobank, born between 1939 and 1970. Information on cancer diagnoses were collected from self-reported data and from national registers until March 2019. Cumulative risk of cancer over the timespan of the study, as measured by the odds ratio (OR), and instantaneous risk, as measured by the hazard ratio (HR), were assessed using Logistic and Cox regression analyses, respectively. The odds were lower among ever users, compared with never users, for ovarian cancer: OR=0.72 (95% CI: 0.65-0.81) and endometrial cancer: OR=0.68 (95% CI: 0.62-0.75), an association that was stronger with longer use (P<0.001). Increased odds were seen for breast cancer in women when limiting the follow-up to 55 years of age: OR=1.10 (95% CI: 1.03-1.17), but not for the full timespan. We only found a higher HR for breast cancer in former users immediately (≤2 years) after discontinued oral contraceptive use (HR=1.55, 95% CI: 1.06-2.28), whereas the protective association for ovarian and endometrial cancer remained significant up to 35 years after last use of oral contraceptives. Given the body of evidence presented in our study, we argue that oral contraceptives can dramatically reduce women's risk of ovarian and endometrial cancer, whereas their effect on lifetime risk of breast cancer is limited.

  • 20.
    Karlsson, Torgny
    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.
    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.
    Pan, Gang
    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.
    Höglund, Julia
    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.
    Wadelius, Claes
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Ek, Weronica E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Johansson, Åsa
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Contribution of genetics to visceral adiposity and its relation to cardiovascular and metabolic disease.2019In: Nature Medicine, ISSN 1078-8956, E-ISSN 1546-170X, Vol. 25, no 9, p. 1390-1395Article in journal (Refereed)
    Abstract [en]

    Visceral adipose tissue (VAT)-fat stored around the internal organs-has been suggested as an independent risk factor for cardiovascular and metabolic disease1-3, as well as all-cause, cardiovascular-specific and cancer-specific mortality4,5. Yet, the contribution of genetics to VAT, as well as its disease-related effects, are largely unexplored due to the requirement for advanced imaging technologies to accurately measure VAT. Here, we develop sex-stratified, nonlinear prediction models (coefficient of determination = 0.76; typical 95% confidence interval (CI) = 0.74-0.78) for VAT mass using the UK Biobank cohort. We performed a genome-wide association study for predicted VAT mass and identified 102 novel visceral adiposity loci. Predicted VAT mass was associated with increased risk of hypertension, heart attack/angina, type 2 diabetes and hyperlipidemia, and Mendelian randomization analysis showed visceral fat to be a causal risk factor for all four diseases. In particular, a large difference in causal effect between the sexes was found for type 2 diabetes, with an odds ratio of 7.34 (95% CI = 4.48-12.0) in females and an odds ratio of 2.50 (95% CI = 1.98-3.14) in males. Our findings bolster the role of visceral adiposity as a potentially independent risk factor, in particular for type 2 diabetes in Caucasian females. Independent validation in other cohorts is necessary to determine whether the findings can translate to other ethnicities, or outside the UK.

  • 21.
    Kierczak, Marcin
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rafati, Nima
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Höglund, Julia
    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.
    Gourlé, Hadrien
    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.
    Lo Faro, Valeria
    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.
    Schmitz, Daniel
    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.
    Ek, Weronica E.
    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.
    Gyllensten, Ulf
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    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.
    Ekman, Diana
    Science for Life Laboratory, Stockholm University, Sweden.
    Nystedt, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    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.
    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.
    Contribution of rare whole-genome sequencing variants to plasma protein levels and the missing heritability2022In: Nature Communications, E-ISSN 2041-1723, Vol. 13, article id 2532Article in journal (Refereed)
    Abstract [en]

    Despite the success of genome-wide association studies, much of the genetic contribution to complex traits remains unexplained. Here, we analysed high coverage whole genome sequencing data, to evaluate the contribution of rare genetic variants to 414 plasma proteins. The frequency distribution of genetic variants was skewed towards the rare spectrum, and damaging variants were more often rare. We estimated that less than 4.3% of the narrow-sense heritability is expected to be explained by rare variants in our cohort. Using a gene-based approach, we identified Cis-associations for 237 of the proteins, which is slightly more compared to a GWAS (N=213), and we identified 34 loci in Trans. Several associations were driven by rare variants, and rare variants had on average larger phenotypic effects. We conclude therefore that rare variants could be of  importance for precision medicine applications, but have a more limited contribution to the missing heritability of complex diseases.

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  • 22.
    Rask-Andersen, Mathias
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ivansson, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Höglund, Julia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ek, Weronica E.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Karlsson, Torgny
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Johansson, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Adiposity and sex-specific cancer risk.2023In: Cancer Cell, ISSN 1535-6108, E-ISSN 1878-3686, Vol. 41, no 6, p. 1186-1197.e4Article in journal (Refereed)
    Abstract [en]

    Obesity is associated with several types of cancer and fat distribution, which differs dramatically between sexes, has been suggested to be an independent risk factor. However, sex-specific effects on cancer risk have rarely been studied. Here we estimate the effects of fat accumulation and distribution on cancer risk in females and males. We performed a prospective study in 442,519 UK Biobank participants, for 19 cancer types and additional histological subtypes, with a mean follow-up time of 13.4 years. Cox proportional hazard models were used to estimate the effect of 14 different adiposity phenotypes on cancer rates, and a 5% false discovery rate was considered statistically significant. Adiposity-related traits are associated with all but three cancer types, and fat accumulation is associated with a larger number of cancers compared to fat distribution. In addition, fat accumulation or distribution exhibit differential effects between sexes on colorectal, esophageal, and liver cancer.

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  • 23.
    Rask-Andersen, Mathias
    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.
    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.
    Ek, Weronica E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Johansson, Asa
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Modification of Heritability for Educational Attainment and Fluid Intelligence by Socioeconomic Deprivation in the UK Biobank2021In: American Journal of Psychiatry, ISSN 0002-953X, E-ISSN 1535-7228, Vol. 178, no 7, p. 625-634Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Socioeconomic factors have been suggested to influence the effect of education- and intelligence-associated genetic variants. However, results from previous studies on the interaction between socioeconomic status and education or intelligence have been inconsistent. The authors sought to assess these interactions in the UK Biobank cohort of 500,000 participants.

    METHODS: The authors assessed the effect of socioeconomic deprivation on education- and intelligence-associated genetic variants by estimating the single-nucleotide polymorphism (SNP) heritability for fluid intelligence, educational attainment, and years of education in subsets of UK Biobank participants with different degrees of social deprivation, using linkage disequilibrium score regression. They also generated polygenic scores with LDpred and tested for interactions with social deprivation.

    RESULTS: SNP heritability increased with socioeconomic deprivation for fluid intelligence, educational attainment, and years of education. Polygenic scores were also found to interact with socioeconomic deprivation, where the effects of the scores increased with increasing deprivation for all traits.

    CONCLUSIONS: These results indicate that genetics have a larger influence on educational and cognitive outcomes in more socioeconomically deprived U.K. citizens, which has serious implications for equality of opportunity.

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

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

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  • 25.
    Rask-Andersen, Mathias
    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.
    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.
    Ek, Weronica E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Johansson, Åsa
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Genome-wide association study of body fat distribution identifies adiposity loci and sex-specific genetic effects2019In: Nature Communications, E-ISSN 2041-1723, Vol. 10, article id 339Article in journal (Refereed)
    Abstract [en]

    Body mass and body fat composition are of clinical interest due to their links to cardiovascular- and metabolic diseases. Fat stored in the trunk has been suggested to be more pathogenic compared to fat stored in other compartments. In this study, we perform genome-wide association studies (GWAS) for the proportion of body fat distributed to the arms, legs and trunk estimated from segmental bio-electrical impedance analysis (sBIA) for 362,499 individuals from the UK Biobank. 98 independent associations with body fat distribution are identified, 29 that have not previously been associated with anthropometric traits. A high degree of sex-heterogeneity is observed and the effects of 37 associated variants are stronger in females compared to males. Our findings also implicate that body fat distribution in females involves mesenchyme derived tissues and cell types, female endocrine tissues as well as extracellular matrix maintenance and remodeling.

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  • 26.
    Schmitz, Daniel
    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.
    Ek, Weronica E.
    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.
    Berggren, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Höglund, Julia
    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.
    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.
    Johansson, Åsa
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Genome-Wide Association Study of Estradiol Levels and the Causal Effect of Estradiol on Bone Mineral Density2021In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 106, no 11, p. e4471-e4486Article in journal (Refereed)
    Abstract [en]

    Context

    Estradiol is the primary female sex hormone and plays an important role for skeletal health in both sexes. Several enzymes are involved in estradiol metabolism, but few genome-wide association studies (GWAS) have been performed to characterize the genetic contribution to variation in estrogen levels.

    Objective

    Identify genetic loci affecting estradiol levels and estimate causal effect of estradiol on bone mineral density (BMD).

    Design

    We performed GWAS for estradiol in males (n = 147 690) and females (n = 163 985) from UK Biobank. Estradiol was analyzed as a binary phenotype above/below detection limit (175 pmol/L). We further estimated the causal effect of estradiol on BMD using Mendelian randomization.

    Results

    We identified 14 independent loci associated (P < 5 × 10−8) with estradiol levels in males, of which 1 (CYP3A7) was genome-wide and 7 nominally (P < 0.05) significant in females. In addition, 1 female-specific locus was identified. Most loci contain functionally relevant genes that have not been discussed in relation to estradiol levels in previous GWAS (eg, SRD5A2, which encodes a steroid 5-alpha reductase that is involved in processing androgens, and UGT3A1 and UGT2B7, which encode enzymes likely to be involved in estradiol elimination). The allele that tags the O blood group at the ABO locus was associated with higher estradiol levels. We identified a causal effect of high estradiol levels on increased BMD in both males (P = 1.58 × 10−11) and females (P = 7.48 × 10−6).

    Conclusion

    Our findings further support the importance of the body’s own estrogen to maintain skeletal health in males and in females.

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  • 27.
    Villarroel, Beatriz
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Observational Astronomy. Uppsala Univ, CIM, SE-75106 Uppsala, Sweden.
    Nyholm, Anders
    Department of Astronomy and The Oskar Klein Centre, Stockholm University, SE-106 91 Stockholm, Sweden.
    Karlsson, Torgny
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Theoretical Astrophysics.
    Comeron, Sebastien
    Univ Oulu, Astron Res Unit, FI-90014 Oulu, Finland.
    Korn, Andreas
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Theoretical Astrophysics.
    Sollerman, Jesper
    Department of Astronomy and The Oskar Klein Centre, Stockholm University, SE-106 91 Stockholm, Sweden.
    Zackrisson, Erik
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Observational Astronomy.
    AGN luminosity and stellar age: two missing ingredients forAGN unification as seen with iPTF supernovae2017In: Astrophysical Journal, ISSN 0004-637X, E-ISSN 1538-4357, Vol. 837, no 2, article id 110Article in journal (Refereed)
    Abstract [en]

    Active galactic nuclei (AGNs) are extremely powerful cosmic objects, driven by accretion of hot gas upon super-massive black holes. The zoo of AGN classes is divided into two major groups, with Type-1 AGNs displaying broad Balmer emission lines and Type-2 narrow ones. For a long time it was believed that a Type-2 AGN is a Type-1 AGN viewed through a dusty kiloparsec-sized torus, but an emerging body of observations suggests more than just the viewing angle matters. Here we report significant differences in supernova (SN) counts and classes in the first study to date of SNe near Type-1 and Type-2 AGN host galaxies, using data from the intermediate Palomar Transient Factory, the Sloan Digital Sky Survey Data Release 7, and Galaxy Zoo. We detect many more SNe in Type-2 AGN hosts (size of effect similar to 5.1 sigma) compared to Type-1 hosts, which shows that the two classes of AGN are located inside host galaxies with different properties. In addition, Type-1 and Type-2 AGNs that are dominated by star formation according to Wide-field Infrared Survey Explorer colors m(W1) - m(W2) < 0.5 and are matched in 22 mu m absolute magnitude differ by a factor of ten in L[O III] lambda 5007 luminosity, suggesting that when residing in similar types of host galaxies Type-1 AGNs are much more luminous. Our results demonstrate two more factors that play an important role in completing the current picture: the age of stellar populations and the AGN luminosity. This has immediate consequences for understanding the many AGN classes and galaxy evolution.

  • 28.
    Villarroel, Beatriz
    et al.
    NORDITA, KTH Royal Inst Technol, Roslagstullsbacken 23, SE-10691 Stockholm, Sweden.;Stockholm Univ, Roslagstullsbacken 23, SE-10691 Stockholm, Sweden.;Inst Astrofis Canarias, Avda Via Lactea S-N, E-38205 Tenerife, Spain..
    Soodla, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Systems and Control.
    Comeron, Sebastien
    Univ Oulu, Astron Res Unit, FI-90014 Oulu, Finland..
    Mattsson, Lars
    NORDITA, KTH Royal Inst Technol, Roslagstullsbacken 23, SE-10691 Stockholm, Sweden.;Stockholm Univ, Roslagstullsbacken 23, SE-10691 Stockholm, Sweden..
    Pelckmans, Kristiaan
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Systems and Control. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Automatic control.
    Lopez-Corredoira, Martin
    Inst Astrofis Canarias, Avda Via Lactea S-N, E-38205 Tenerife, Spain.;Univ La Laguna, Dept Astrofis, E-38206 Tenerife, Spain..
    Krisciunas, Kevin
    Texas A&M Univ, Dept Phys & Astron, 4242 TAMU, College Stn, TX 77843 USA..
    Guerras, Eduardo
    Univ Oklahoma, Homer L Dodge Dept Phys & Astron, Norman, OK 73019 USA..
    Kochukhov, Oleg
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Observational Astronomy.
    Bergstedt, Josefine
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Observational Astronomy.
    Buelens, Bart
    Methodol Dept, Stat Netherlands, Heerlen, Netherlands.;VITO, Diepenbeek Genk, Flanders, Belgium..
    Bar, Rudolf E.
    Swiss Fed Inst Technol, Inst Particle Phys & Astrophys, Wolfgang Pauli Str 27, CH-8093 Zurich, Switzerland..
    Cubo, Rubén
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Systems and Control. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Automatic control.
    Emilio Enriquez, J.
    Univ Calif Berkeley, Dept Astron, 501 Campbell Hall 311, Berkeley, CA 94720 USA..
    Gupta, Alok C.
    Aryabhatta Res Inst Observat Sci ARIES, Manora Peak 263002, Nainital, India..
    Imaz, Inigo
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Observational Astronomy.
    Karlsson, Torgny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Almudena Prieto, M.
    Inst Astrofis Canarias, Avda Via Lactea S-N, E-38205 Tenerife, Spain.;Univ La Laguna, Dept Astrofis, E-38206 Tenerife, Spain..
    Shlyapnikov, Aleksey A.
    Stellar Phys Dept, Crimean, Ukraine. Astrophys Observ, UA-298409 Nauchnyj, Crimea, Ukraine..
    de Souza, Rafael S.
    Univ N Carolina, Dept Phys & Astron, Chapel Hill, NC 27599 USA..
    Vavilova, Irina B.
    NAS Ukraine, Main Astron Observ, 27 Akad Zabolotny St, UA-03143 Kiev, Ukraine..
    Ward, Martin J.
    Univ Durham, Dept Phys, Ctr Extragalact Astron, South Rd, Durham DH1 3LE, England..
    The Vanishing and Appearing Sources during a Century of Observations Project. I. USNO Objects Missing in Modern Sky Surveys and Follow-up Observations of a "Missing Star"2020In: Astronomical Journal, ISSN 0004-6256, E-ISSN 1538-3881, Vol. 159, no 1, article id 8Article in journal (Refereed)
    Abstract [en]

    In this paper we report the current status of a new research program. The primary goal of the "Vanishing and Appearing Sources during a Century of Observations" project is to search for vanishing and appearing sources using existing survey data to find examples of exceptional astrophysical transients. The implications of finding such objects extend from traditional astrophysics fields to the more exotic searches for evidence of technologically advanced civilizations. In this first paper we present new, deeper observations of the tentative candidate discovered by Villarroel et al. in 2016. We then perform the first searches for vanishing objects throughout the sky by comparing 600 million objects from the US Naval Observatory Catalogue (USNO) B1.0 down to a limiting magnitude of similar to 20-21 with the recent Pan-STARRS Data Release-1 (DR1) with a limiting magnitude of similar to 23.4. We find about 150,000 preliminary candidates that do not have any Pan-STARRS counterpart within a 30 '' radius. We show that these objects are redder and have larger proper motions than typical USNO objects. We visually examine the images for a subset of about 24,000 candidates, superseding the 2016 study with a sample 10 times larger. We find about 100 point sources visible in only one epoch in the red band of the USNO, which may be of interest in searches for strong M-dwarf flares, high-redshift supernovae, or other categories of unidentified red transients.

  • 29. Zhang, L.
    et al.
    Karlsson, Torgny
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Theoretical Astrophysics.
    Christlieb, N.
    Korn, Andreas
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Theoretical Astrophysics.
    Barklem, Paul
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Theoretical Astrophysics.
    Zhao, G.
    HERES VI. Galactic chemical evolution of Si and C (Zhang+, 2011)2011In: VizieR Online Data Catalog, Vol. 352Article in journal (Refereed)
    Abstract [en]

    The present work is based on the spectra of 253 HERES stars. The sample selection and observations are described in Christlieb et al. (2004A\ampA...428.1027C). For the convenience of the reader, we repeat here that the spectra were obtained with the Ultraviolet-Visual Echelle Spectrograph (UVES) mounted on the 8m Unit Telescope 2 (Kueyen) of the Very Large Telescope (VLT). (1 data file).

1 - 29 of 29
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