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

By Josine L. Min, Gibran Hemani, Eilis Hannon, Koen F Dekkers, Juan Castillo-Fernandez, René Luijk, Elena Carnero-Montoro, Daniel J Lawson, Kimberley Burrows, Matthew Suderman, Andrew D Breterick, 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-Tárraga, Eva Giralt-Steinhauer, 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 Bollepalli, 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, BIOS Consortium, Chris Shaw, Ammar Al Chalabi, Susan M. Ring, Göran Pershagen, Erik Melén, Jordi Jiménez-Conde, Jaume Roquer, Debbie A Lawlor, John Wright, Nicholas G Martin, Grant W. Montgomery, Terrie E. Moffitt, Richie Poulton, Tonu Esko, Lili Milani, Andres Metspalu, John R.B. Perry, Ken K. Ong, Nicholas J Wareham, Giuseppe Matullo, Carlotta Sacerdote, Avshalom Caspi, Louise Arseneault, France Gagnon, Miina Ollikainen, Jaakko Kaprio, Janine F. Felix, Fernando Rivadeneira, Henning Tiemeier, Marinus H. van IJzendoorn, André G. Uitterlinden, Vincent W.V. Jaddoe, Chris Haley, Andrew M McIntosh, Kathryn L Evans, Alison Murray, Katri Räikkönen, Jari Lathi, Ellen A Nohr, Thorkild IA Sørensen, Torben Hansen, Camilla Schmidt 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 Morange, David-Alexandre Trégouët, Jan H. Veldink, Gareth E. Davies, Eco JC de Geus, Dorret I Boomsma, Judith M. Vonk, Bert Brunekreef, Gerard H Koppelman, Marta E. Alarcón-Riquelme, Rae-Chi Huang, Craig Pennell, Joyce van Meurs, Mohammad 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 Relton

Posted 03 Sep 2020
medRxiv DOI: 10.1101/2020.09.01.20180406

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 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.

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