Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation

• Type of Material: Article
• Authors: Elisabeth Binder, Emory University; Meena Kumari, Emory University
• Language: English
• Date: 2021-09-01
• Publisher: Nature Research
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use
• Final Published Version (URL): http://dx.doi.org/10.1038/s41588-021-00923-x
• Title of Journal or Parent Work: NATURE GENETICS
• Volume: 53
• Issue: 9
• Start Page: 1311
• End Page: 1321
• Grant/Funding Information: C.L.R., G.D.S., G.S., J.L.M., K.B., M.Su., T.G.R. and T.R.G. are supported by the UK Medical Research Council (MRC) Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/1, MC_UU_00011/4, MC_UU_00011/5). C.L.R. receives support from a Cancer Research UK Programme Grant (C18281/A19169). G.H. is funded by the Wellcome Trust and the Royal Society (208806/Z/17/Z). E.H. and J.M. were supported by MRC project grants (MR/K013807/1 and MR/R005176/1 awarded to J.M.) and a MRC Clinical Infrastructure award (MR/M008924/1 awarded to J.M.). B.T.H. is supported by the Netherlands CardioVascular Research Initiative (the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organisation for Health Research and Development, and the Royal Netherlands Academy of Sciences) for the GENIUS project Generating the best evidence-based pharmaceutical targets for atherosclerosis (CVON2011-19, CVON2017-20). J.T.B. was supported by the Economic and Social Research Council (ES/N000404/1). The study was also supported by JPI HDHL funded DIMENSION project (administered by the Biotechnology and Biological Sciences Research Council, BB/S020845/1 to J.T.B., and by ZonMW The Netherlands, grant 529051021 to B.T.H). A.D.B. has been supported by a Wellcome Trust PhD Training Fellowship for Clinicians, the Edinburgh Clinical Academic Track programme (204979/Z/16/Z). J.Kl. was supported by a DOC fellowship of the Austrian Academy of Sciences.
• Research Categories: Biology, Genetics

Abstract

Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. Here we describe results of DNA methylation-quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites we construct networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype-phenotype map than previously anticipated.