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

• DOI: 10.1038/s41588-021-00923-x
• Publication Date: 2021-09-07T15:03:37Z
• Authors: Josine L. Min; Gibran Hemani; Eilis Hannon; Koen F. Dekkers; Juan Castillo-Fer...; René Luijk; Elena Carnero-Mon...; Daniel J. Lawson; Kimberley Burrows; Matthew Suderman; Andrew D. Bretherick; Tom G. Richardson; Johanna Klughammer; Valentina Iotchkova; Gemma Sharp; Ahmad Al Khleifat; Aleksey Shatunov; Alfredo Iacoangeli; Wendy L. McArdle; Karen M. Ho; Ashish Kumar; Cilla Söderhäll; Carolina Soriano-...; Eva Giralt-Steinh...; Nabila Kazmi; Dan Mason; Allan F. McRae; David L. Corcoran; Karen Sugden; Silva Kasela; Alexia Cardona; Felix R. Day; Giovanni Cugliari; Clara Viberti; Simonetta Guarrera; Michael Lerro; Richa Gupta; Sailalitha Bollep...; Pooja Mandaviya; Yanni Zeng; Toni-Kim Clarke; Rosie M. Walker; Vanessa Schmoll; Darina Czamara; Carlos Ruiz-Arenas; Faisal I. Rezwan; Riccardo E. Marioni; Tian Lin; Yvonne Awaloff; Marine Germain; Dylan Aïssi; Ramona Zwamborn; Kristel van Eijk; Annelot Dekker; Jenny van Dongen; Jouke-Jan Hottenga; Gonneke Willemsen; Cheng-Jian Xu; Guillermo Barturen; Francesc Català-Moll; Martin Kerick; Carol Wang; Phillip Melton; Hannah R. Elliott; Jean Shin; Manon Bernard; Idil Yet; Melissa Smart; Tyler Gorrie-Stone; ; Chris Shaw; Ammar Al Chalabi; Susan M. Ring; Göran Pershagen; Erik Melén; Jordi Jiménez-Conde; Jaume Roquer; Deborah A. Lawlor; John Wright; Nicholas G. Martin; Grant W. Montgomery; Terrie E. Moffitt; Richie Poulton; Tõnu Esko; Lili Milani; Andres Metspalu; John R. B. Perry; Ken K. Ong; Nicholas J. Wareham; Giuseppe Matullo; Carlotta Sacerdote; Salvatore Panico; Avshalom Caspi; Louise Arseneault; France Gagnon; Miina Ollikainen; Jaakko Kaprio; Janine F. Felix; Fernando Rivadeneira; Henning Tiemeier; Marinus H. van IJ...; André G. Uitterli...; Vincent W. V. Jaddoe; Chris Haley; Andrew M. McIntosh; Kathryn L. Evans; Alison Murray; Katri Räikkönen; Jari Lahti; Ellen A. Nohr; Thorkild I. A. Sø...; Torben Hansen; Camilla S. Morgen; Elisabeth B. Binder; Susanne Lucae; Juan Ramon Gonzalez; Mariona Bustamante; Jordi Sunyer; John W. Holloway; Wilfried Karmaus; Hongmei Zhang; Ian J. Deary; Naomi R. Wray; John M. Starr; Marian Beekman; Diana van Heemst; P. Eline Slagboom; Pierre-Emmanuel M...; David-Alexandre T...; Jan H. Veldink; Gareth E. Davies; Eco J. C. de Geus; Dorret I. Boomsma; Judith M. Vonk; Bert Brunekreef; Gerard H. Koppelman; Marta E. Alarcón-...; Rae-Chi Huang; Craig E. Pennell; Joyce van Meurs; M. Arfan Ikram; Alun D. Hughes; Therese Tillin; Nish Chaturvedi; Zdenka Pausova; Tomas Paus; Timothy D. Spector; Meena Kumari; Leonard C. Schalkwyk; Peter M. Visscher; George Davey Smith; Christoph Bock; Tom R. Gaunt; Jordana T. Bell; Bastiaan T. Heijmans; Jonathan Mill; Caroline L. Relton
• Keywords: EMC MM-04-54-08-A; 570; Multifactorial Inheritance; ADN; Quantitative Trait Loci; Polymorphism, Single Nucleotide; Article; Epigenesis, Genetic; 03 medical and health sciences; Quantitative Trait, Heritable; Genetics; Humans; Genetic Predisposition to Disease; Genotip; 0303 health sciences; Chromosome Mapping; DNA; DNA Methylation; Fenotip; Gene Expression Regulation; [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie; Metilació; Transcriptome; Genètica; Genome-Wide Association Study

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.