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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
Authors/Creators:	Min, JL and Hemani, G and Hannon, E and Dekkers, KF and Castillo-Fernandez, J and Luijk, R and Carnero-Montoro, E and Lawson, DJ and Burrows, K and Suderman, M and Bretherick, AD and Richardson, TG and Klughammer, J and Iotchkova, V and Sharp, G and Al Khleifat, A and Shatunov, A and Iacoangeli, A and McArdle, WL and Ho, KM and Kumar, A and Soderhall, C and Soriano-Tarraga, C and Giralt-Steinhauer, E and Kazmi, N and Mason, D and McRae, AF and Corcoran, DL and Sugden, K and Kasela, S and Cardona, A and Day, FR and Cugliari, G and Viberti, C and Guarrera, S and Lerro, M and Gupta, R and Bollepalli, S and Mandaviya, P and Zeng, Y and Clarke, TK and Walker, RM and Schmoll, V and Czamara, D and Ruiz-Arenas, C and Rezwan, FI and Marioni, RE and Lin, T and Awaloff, Y and Germain, M and Aissi, D and Zwamborn, R and van Eijk, K and Dekker, A and van Dongen, J and Hottenga, JJ and Willemsen, G and Xu, CJ and Barturen, G and Catala-Moll, F and Kerick, M and Wang, C and Melton, P and Elliott, HR and Shin, J and Bernard, M and Yet, I and Smart, M and Gorrie-Stone, T and Shaw, C and Al Chalabi, A and Ring, SM and Pershagen, G and Melen, E and Jimenez-Conde, J and Roquer, J and Lawlor, DA and Wright, J and Martin, NG and Montgomery, GW and Moffitt, TE and Poulton, R and Esko, T and Milani, L and Metspalu, A and Perry, JRB and Ong, KK and Wareham, NJ and Matullo, G and Sacerdote, C and Panico, S and Caspi, A and Arseneault, L and Gagnon, F and Ollikainen, M and Kaprio, J and Felix, JF and Rivadeneira, F and Tiemeier, H and van IJzendoorn, MH
Keywords:	DNA methylation, genetic influences, DNAm
Journal or Publication Title:	Nature Genetics
Publisher:	Nature Publishing Group
ISSN:	1061-4036
DOI / ID Number:	https://doi.org/10.1038/s41588-021-00923-x
Copyright Information:	Copyright 2021 Nature Publishing Group
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