Genomic and phenomic insights from an atlas of genetic effects on DNA methylation
Authors: Min Josine L. , Hemani Gibran , Hannon Eilis , Dekkers Koen F. , Castillo-Fernandez Juan , Luijk René , Carnero-Montoro Elena , Lawson Daniel J. , Burrows Kimberley , Suderman Matthew , Bretherick Andrew D. , Richardson Tom G , Klughammer Johanna , Iotchkova Valentina , Sharp Gemma , Khleifat Ahmad Al , Shatunov Aleksey , Iacoangeli Alfredo , McArdle Wendy L , Ho Karen M , Kumar Ashish , Söderhäll Cilla , Soriano-Tárraga Carolina , Giralt-Steinhauer Eva , Kazmi Nabila , Mason Dan , McRae Allan F , Corcoran David L , Sugden Karen , Kasela Silva , Cardona Alexia , Day Felix R. , Cugliari Giovanni , Viberti Clara , Guarrera Simonetta , Lerro Michael , Gupta Richa , Bollepalli Sailalitha , Mandaviya Pooja , Zeng Yanni , Clarke Toni-Kim , Walker Rosie M , Schmoll Vanessa , Czamara Darina , Ruiz-Arenas Carlos , Rezwan Faisal I , Marioni Riccardo E , Lin Tian , Awaloff Yvonne , Germain Marine , Aïssi Dylan , Zwamborn Ramona , Eijk Kristel van , Dekker Annelot , Dongen Jenny van , Hottenga Jouke-Jan , Willemsen Gonneke , Xu Cheng-Jian , Barturen Guillermo , Català-Moll Francesc , Kerick Martin , Wang Carol , Melton Phillip , Elliott Hannah R , Shin Jean , Bernard Manon , Yet Idil , Smart Melissa , Gorrie-Stone Tyler ,   BIOS Consortium, Shaw Chris , Chalabi Ammar Al , Ring Susan M , Pershagen Göran , Melén Erik , Jiménez-Conde Jordi , Roquer Jaume , Lawlor Debbie A , Wright John , Martin Nicholas G , Montgomery Grant W , Moffitt Terrie E , Poulton Richie , Esko Tõnu , Milani Lili , Metspalu Andres , Perry John R. B. , Ong Ken K. , Wareham Nicholas J , Matullo Giuseppe , Sacerdote Carlotta , Caspi Avshalom , Arseneault Louise , Gagnon France , Ollikainen Miina , Kaprio Jaakko , Felix Janine F , Rivadeneira Fernando , Tiemeier Henning , IJzendoorn Marinus H van , Uitterlinden André G , Jaddoe Vincent WV , Haley Chris , McIntosh Andrew M , Evans Kathryn L , Murray Alison , Räikkönen Katri , Lahti Jari , Nohr Ellen A , Sørensen Thorkild IA , Hansen Torben , Morgen Camilla Schmidt , Binder Elisabeth B , Lucae Susanne , Gonzalez Juan Ramon , Bustamante Mariona , Sunyer Jordi , Holloway John W , Karmaus Wilfried , Zhang Hongmei , Deary Ian J , Wray Naomi R , Starr John M , Beekman Marian , Heemst Diana van , Slagboom P Eline , Morange Pierre-Emmanuel , Trégouët David-Alexandre , Veldink Jan H. , Davies Gareth E , Geus Eco JC de , Boomsma Dorret I , Vonk Judith M , Brunekreef Bert , Koppelman Gerard H. , Alarcón-Riquelme Marta E , Huang Rae-Chi , Pennell Craig , Meurs Joyce van , Ikram M. Arfan , Hughes Alun D , Tillin Therese , Chaturvedi Nish , Pausova Zdenka , Paus Tomas , Spector Timothy D , Kumari Meena , Schalkwyk Leonard C , Visscher Peter M , Smith George Davey , Bock Christoph , Gaunt Tom R , Bell Jordana T , Heijmans Bastiaan T. , Mill Jonathan , Relton Caroline L 
Published: September 2020

AbstractCharacterizing 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 loci (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 mQTL of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We reveal that the genetic architecture of DNAm levels is highly polygenic and DNAm exhibits signatures of negative and positive natural selection. 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 factors are associated with both blood DNAm levels and complex diseases but in most cases these associations do not reflect causal relationships from DNAm to trait or vice versa indicating a more complex genotype-phenotype map than has previously been hypothesised.