TY - JOUR
T1 - Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation
AU - BIOS Consortium
AU - Min, Josine L.
AU - Hemani, Gibran
AU - Hannon, Eilis
AU - Dekkers, Koen F.
AU - Castillo-Fernandez, Juan
AU - Luijk, René
AU - Carnero-Montoro, Elena
AU - Lawson, Daniel J.
AU - Burrows, Kimberley
AU - Suderman, Matthew
AU - Bretherick, Andrew D.
AU - Richardson, Tom G.
AU - Klughammer, Johanna
AU - Iotchkova, Valentina
AU - Sharp, Gemma
AU - Al Khleifat, Ahmad
AU - Shatunov, Aleksey
AU - Iacoangeli, Alfredo
AU - McArdle, Wendy L.
AU - Ho, Karen M.
AU - Kumar, Ashish
AU - Söderhäll, Cilla
AU - Soriano-Tárraga, Carolina
AU - Giralt-Steinhauer, Eva
AU - Kazmi, Nabila
AU - Mason, Dan
AU - McRae, Allan F.
AU - Corcoran, David L.
AU - Sugden, Karen
AU - Kasela, Silva
AU - Cardona, Alexia
AU - Day, Felix R.
AU - Cugliari, Giovanni
AU - Viberti, Clara
AU - Guarrera, Simonetta
AU - Lerro, Michael
AU - Gupta, Richa
AU - Bollepalli, Sailalitha
AU - Mandaviya, Pooja
AU - Zeng, Yanni
AU - Clarke, Toni Kim
AU - Walker, Rosie M.
AU - Schmoll, Vanessa
AU - Yet, Idil
AU - Al Chalabi, Ammar
AU - Caspi, Avshalom
AU - Arseneault, Louise
AU - Spector, Timothy D.
AU - Schalkwyk, Leonard C.
AU - Bell, Jordana T.
N1 - Funding Information:
C.L.R., G.D.S., G.S., J.L.M., K.B., M. Suderman, 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 (no. C18281/A191169). 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 (nos. MR/K013807/1 and MR/R005176/1 to J.M.) and an MRC Clinical Infrastructure award (no. MR/M008924/1 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 (grant no. ES/N000404/1). The present study was also supported by JPI HDHL-funded DIMENSION project (administered by the BBSRC UK, grant no. BB/S020845/1 to J.T.B., and by ZonMW the Netherlands, grant no. 529051021 to B.T.H). A.D.B. has been supported by a Wellcome Trust PhD Training Fellowship for Clinicians and the Edinburgh Clinical Academic Track programme (204979/Z/16/Z). J. Klughammer was supported by a DOC fellowship of the Austrian Academy of Sciences. Cohort-specific acknowledgements and funding are presented in the Supplementary Note.
Funding Information:
T.R.G. receives funding from GlaxoSmithKline and Biogen for unrelated research. The other authors declare no competing interests.
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/9
Y1 - 2021/9
N2 - Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm 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 constructed 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.
AB - Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm 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 constructed 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.
UR - http://www.scopus.com/inward/record.url?scp=85103124472&partnerID=8YFLogxK
U2 - 10.1038/s41588-021-00923-x
DO - 10.1038/s41588-021-00923-x
M3 - Article
AN - SCOPUS:85103124472
SN - 1061-4036
VL - 53
SP - 1311
EP - 1321
JO - Nature Genetics
JF - Nature Genetics
IS - 9
ER -