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 - Czamara, Darina
AU - Ruiz-Arenas, Carlos
AU - Rezwan, Faisal I.
AU - Marioni, Riccardo E.
AU - Lin, Tian
AU - Awaloff, Yvonne
AU - Germain, Marine
AU - Aïssi, Dylan
AU - Zwamborn, Ramona
AU - van Eijk, Kristel
AU - Dekker, Annelot
AU - van Dongen, Jenny
AU - Hottenga, Jouke Jan
AU - Willemsen, Gonneke
AU - Xu, Cheng Jian
AU - Barturen, Guillermo
AU - Català-Moll, Francesc
AU - Kerick, Martin
AU - Wang, Carol
AU - Melton, Phillip
AU - Elliott, Hannah R.
AU - Shin, Jean
AU - Bernard, Manon
AU - Yet, Idil
AU - Smart, Melissa
AU - Gorrie-Stone, Tyler
AU - Shaw, Chris
AU - Al Chalabi, Ammar
AU - Ring, Susan M.
AU - Pershagen, Göran
AU - Melén, Erik
AU - Jiménez-Conde, Jordi
AU - Roquer, Jaume
AU - Lawlor, Deborah A.
AU - Wright, John
AU - Martin, Nicholas G.
AU - Montgomery, Grant W.
AU - Moffitt, Terrie E.
AU - Poulton, Richie
AU - Esko, Tõnu
AU - Milani, Lili
AU - Metspalu, Andres
AU - Perry, John R.B.
AU - Ong, Ken K.
AU - Wareham, Nicholas J.
AU - Matullo, Giuseppe
AU - Sacerdote, Carlotta
AU - Panico, Salvatore
AU - Caspi, Avshalom
AU - Arseneault, Louise
AU - Gagnon, France
AU - Ollikainen, Miina
AU - Kaprio, Jaakko
AU - Felix, Janine F.
AU - Rivadeneira, Fernando
AU - Tiemeier, Henning
AU - van IJzendoorn, Marinus H.
AU - Uitterlinden, André G.
AU - Jaddoe, Vincent W.V.
AU - Haley, Chris
AU - McIntosh, Andrew M.
AU - Evans, Kathryn L.
AU - Murray, Alison
AU - Räikkönen, Katri
AU - Lahti, Jari
AU - Nohr, Ellen A.
AU - Sørensen, Thorkild I.A.
AU - Hansen, Torben
AU - Morgen, Camilla S.
AU - Binder, Elisabeth B.
AU - Lucae, Susanne
AU - Gonzalez, Juan Ramon
AU - Bustamante, Mariona
AU - Sunyer, Jordi
AU - Holloway, John W.
AU - Karmaus, Wilfried
AU - Zhang, Hongmei
AU - Deary, Ian J.
AU - Wray, Naomi R.
AU - Starr, John M.
AU - Beekman, Marian
AU - van Heemst, Diana
AU - Slagboom, P. Eline
AU - Morange, Pierre Emmanuel
AU - Trégouët, David Alexandre
AU - Veldink, Jan H.
AU - Davies, Gareth E.
AU - de Geus, Eco J.C.
AU - Boomsma, Dorret I.
AU - Vonk, Judith M.
AU - Brunekreef, Bert
AU - Koppelman, Gerard H.
AU - Alarcón-Riquelme, Marta E.
AU - Huang, Rae Chi
AU - Pennell, Craig E.
AU - van Meurs, Joyce
AU - Ikram, M. Arfan
AU - Hughes, Alun D.
AU - Tillin, Therese
AU - Chaturvedi, Nish
AU - Pausova, Zdenka
AU - Paus, Tomas
AU - Spector, Timothy D.
AU - Kumari, Meena
AU - Schalkwyk, Leonard C.
AU - Visscher, Peter M.
AU - Davey Smith, George
AU - Bock, Christoph
AU - Gaunt, Tom R.
AU - Bell, Jordana T.
AU - Heijmans, Bastiaan T.
AU - Mill, Jonathan
AU - Relton, Caroline L.
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.
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
C2 - 34493871
AN - SCOPUS:85103124472
VL - 53
SP - 1311
EP - 1321
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 9
ER -