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

Min, Josine L and Hemani, Gibran and Hannon, Eilis and Dekkers, Koen F and Castillo-Fernandez, Juan and Luijk, René and Carnero-Montoro, Elena and Lawson, Daniel J and Burrows, Kimberley and Suderman, Matthew and Bretherick, Andrew D and Richardson, Tom G and Klughammer, Johanna and Iotchkova, Valentina and Sharp, Gemma and Al Khleifat, Ahmad and Shatunov, Aleksey and Iacoangeli, Alfredo and McArdle, Wendy L and Ho, Karen M and Kumar, Ashish and Söderhäll, Cilla and Soriano-Tárraga, Carolina and Giralt-Steinhauer, Eva and Kazmi, Nabila and Mason, Dan and McRae, Allan F and Corcoran, David L and Sugden, Karen and Kasela, Silva and Cardona, Alexia and Day, Felix R and Cugliari, Giovanni and Viberti, Clara and Guarrera, Simonetta and Lerro, Michael and Gupta, Richa and Bollepalli, Sailalitha and Mandaviya, Pooja and Zeng, Yanni and Clarke, Toni-Kim and Walker, Rosie M and Schmoll, Vanessa and Czamara, Darina and Ruiz-Arenas, Carlos and Rezwan, Faisal I and Marioni, Riccardo E and Lin, Tian and Awaloff, Yvonne and Germain, Marine and Aïssi, Dylan and Zwamborn, Ramona and van Eijk, Kristel and Dekker, Annelot and van Dongen, Jenny and Hottenga, Jouke-Jan and Willemsen, Gonneke and Xu, Cheng-Jian and Barturen, Guillermo and Català-Moll, Francesc and Kerick, Martin and Wang, Carol and Melton, Phillip and Elliott, Hannah R and Shin, Jean and Bernard, Manon and Yet, Idil and Smart, Melissa and Gorrie-Stone, Tyler and Shaw, Chris and Al Chalabi, Ammar and Ring, Susan M and Pershagen, Göran and Melén, Erik and Jiménez-Conde, Jordi and Roquer, Jaume and Lawlor, Deborah A and Wright, John and Martin, Nicholas G and Montgomery, Grant W and Moffitt, Terrie E and Poulton, Richie and Esko, Tõnu and Milani, Lili and Metspalu, Andres and Perry, John RB and Ong, Ken K and Wareham, Nicholas J and Matullo, Giuseppe and Sacerdote, Carlotta and Panico, Salvatore and Caspi, Avshalom and Arseneault, Louise and Gagnon, France and Ollikainen, Miina and Kaprio, Jaakko and Felix, Janine F and Rivadeneira, Fernando and Tiemeier, Henning and van IJzendoorn, Marinus H and Uitterlinden, André G and Jaddoe, Vincent WV and Haley, Chris and McIntosh, Andrew M and Evans, Kathryn L and Murray, Alison and Räikkönen, Katri and Lahti, Jari and Nohr, Ellen A and Sørensen, Thorkild IA and Hansen, Torben and Morgen, Camilla S and Binder, Elisabeth B and Lucae, Susanne and Gonzalez, Juan Ramon and Bustamante, Mariona and Sunyer, Jordi and Holloway, John W and Karmaus, Wilfried and Zhang, Hongmei and Deary, Ian J and Wray, Naomi R and Starr, John M and Beekman, Marian and van Heemst, Diana and Slagboom, P Eline and Morange, Pierre-Emmanuel and Trégouët, David-Alexandre and Veldink, Jan H and Davies, Gareth E and de Geus, Eco JC and Boomsma, Dorret I and Vonk, Judith M and Brunekreef, Bert and Koppelman, Gerard H and Alarcón-Riquelme, Marta E and Huang, Rae-Chi and Pennell, Craig E and van Meurs, Joyce and Ikram, M Arfan and Hughes, Alun D and Tillin, Therese and Chaturvedi, Nish and Pausova, Zdenka and Paus, Tomas and Spector, Timothy D and Kumari, Meena and Schalkwyk, Leonard C and Visscher, Peter M and Davey Smith, George and Bock, Christoph and Gaunt, Tom R and Bell, Jordana T and Heijmans, Bastiaan T and Mill, Jonathan and Relton, Caroline L (2021) 'Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation.' Nature Genetics, 53 (9). pp. 1311-1321. ISSN 1061-4036

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Abstract

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.

Item Type: Article
Uncontrolled Keywords: Epigenetics; Genetics research
Divisions: Faculty of Science and Health
Faculty of Science and Health > Life Sciences, School of
Faculty of Social Sciences
Faculty of Social Sciences > Institute for Social and Economic Research
SWORD Depositor: Elements
Depositing User: Elements
Date Deposited: 03 Dec 2021 16:24
Last Modified: 06 Mar 2022 02:00
URI: http://repository.essex.ac.uk/id/eprint/31704

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