Integrative analysis of gene expression, DNA methylation, physiological traits, and genetic variation in human skeletal muscle

Proceedings of the National Academy of Sciences of the United States of America - Tập 116 Số 22 - Trang 10883-10888 - 2019
D. Leland Taylor1,2, Anne Jackson3,4, Narisu Narisu5, Gibran Hemani6, Michael R. Erdos5, Peter S. Chines5, Amy J. Swift5, Jackie Idol5, John P. Didion5, Ryan Welch3,4, Leena Kinnunen7, Jouko Saramies8, Timo A. Lakka9,10,11, Markku Laakso12,13, Jaakko Tuomilehto14,15,16, Stephen C. J. Parker17,18, Heikki A. Koistinen19,20,21, George Davey Smith6, Michael Boehnke3,4, Laura J. Scott3,4, Ewan Birney1, Francis S. Collins5
1European Molecular Biology Laboratory, European Bioinformatics Institute, CB10 1SD Hinxton, United Kingdom;
2European Molecular Biology Laboratory, European Bioinformatics Institute, CB10 1SD Hinxton, United Kingdom;; Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892;
3Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109;
4Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI 48109
5Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892;
6MRC Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, BS8 2BN Bristol, United Kingdom;
7Department of Public Health Solutions, National Institute for Health and Welfare, FI-00271 Helsinki, Finland;
8Rehabilitation Center, South Karelia Social and Health Care District EKSOTE, Fl-53130 Lappeenranta, Finland;
9Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Fl-70211 Kuopio, Finland;
10Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Fl-70211 Kuopio, Finland;; Foundation for Research in Health Exercise and Nutrition, Kuopio Research Institute of Exercise Medicine, Fl-70100 Kuopio, Finland;; Institute of Biomedicine, School of Medicine, University of Eastern Finland, Fl-70211 Kuopio, Finland;
11Foundation for Research in Health Exercise and Nutrition, Kuopio Research Institute of Exercise Medicine, Fl-70100 Kuopio, Finland;
12Department of Medicine, Kuopio University Hospital, FI-70210 Kuopio, Finland;
13Department of Medicine, Kuopio University Hospital, FI-70210 Kuopio, Finland;; Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, FI-70210 Kuopio, Finland;
14Department of Public Health Solutions, National Institute for Health and Welfare, FI-00271 Helsinki, Finland;; Department of Public Health, University of Helsinki, Fl-00014 Helsinki, Finland;; Saudi Diabetes Research Group, King Abdulaziz University, 21589 Jeddah, Saudi Arabia;
15Department of Public Health, University of Helsinki, Fl-00014 Helsinki, Finland;
16Saudi Diabetes Research Group, King Abdulaziz University, 21589 Jeddah, Saudi Arabia
17Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI 48109;
18Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109
19Department of Medicine, University of Helsinki and Helsinki University Central Hospital, FI-00029 Helsinki, Finland;
20Department of Medicine, University of Helsinki and Helsinki University Central Hospital, FI-00029 Helsinki, Finland;; Department of Public Health Solutions, National Institute for Health and Welfare, FI-00271 Helsinki, Finland;; Minerva Foundation Institute for Medical Research, FI-00290 Helsinki, Finland
21Minerva Foundation Institute for Medical Research, FI-00290 Helsinki, Finland

Tóm tắt

We integrate comeasured gene expression and DNA methylation (DNAme) in 265 human skeletal muscle biopsies from the FUSION study with >7 million genetic variants and eight physiological traits: height, waist, weight, waist–hip ratio, body mass index, fasting serum insulin, fasting plasma glucose, and type 2 diabetes. We find hundreds of genes and DNAme sites associated with fasting insulin, waist, and body mass index, as well as thousands of DNAme sites associated with gene expression (eQTM). We find that controlling for heterogeneity in tissue/muscle fiber type reduces the number of physiological trait associations, and that long-range eQTMs (>1 Mb) are reduced when controlling for tissue/muscle fiber type or latent factors. We map genetic regulators (quantitative trait loci; QTLs) of expression (eQTLs) and DNAme (mQTLs). Using Mendelian randomization (MR) and mediation techniques, we leverage these genetic maps to predict 213 causal relationships between expression and DNAme, approximately two-thirds of which predict methylation to causally influence expression. We use MR to integrate FUSION mQTLs, FUSION eQTLs, and GTEx eQTLs for 48 tissues with genetic associations for 534 diseases and quantitative traits. We identify hundreds of genes and thousands of DNAme sites that may drive the reported disease/quantitative trait genetic associations. We identify 300 gene expression MR associations that are present in both FUSION and GTEx skeletal muscle and that show stronger evidence of MR association in skeletal muscle than other tissues, which may partially reflect differences in power across tissues. As one example, we find that increased RXRA muscle expression may decrease lean tissue mass.

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Proceedings of the National Academy of Sciences of the United States of America

Tập 116 Số 22

10883-10888

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