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

Min, J. L.; Hemani, G.; Hannon, E.; Dekkers, K. F.; Castillo-Fernandez, J.; Luijk, R.; Carnero-Montoro, E.; Lawson, D. J.; Burrows, K.; Suderman, M.; Bretherick, A. D.; Richardson, T. G.; Klughammer, J.; Iotchkova, V.; Sharp, G.; Al Khleifat, A.; Shatunov, A.; Iacoangeli, A.; Mcardle, W. L.; K. M., Ho; Kumar, A.; Soderhall, C.; Soriano-Tarraga, C.; Giralt-Steinhauer, E.; Kazmi, N.; Mason, D.; Mcrae, A. F.; Corcoran, D. L.; Sugden, K.; Kasela, S.; Cardona, A.; Day, F. R.; Cugliari, G.; Viberti, C.; Guarrera, S.; Lerro, M.; Gupta, R.; Bollepalli, S.; Mandaviya, P.; Zeng, Y.; Clarke, T. -K.; Walker, R. M.; Schmoll, V.; Czamara, D.; Ruiz-Arenas, C.; Rezwan, F. I.; Marioni, R. E.; Lin, T.; Awaloff, Y.; Germain, M.; Aissi, D.; Zwamborn, R.; van Eijk, K.; Dekker, A.; van Dongen, J.; Hottenga, J. -J.; Willemsen, G.; C. -J., Xu; Barturen, G.; Catala-Moll, F.; Kerick, M.; Wang, C.; Melton, P.; Elliott, H. R.; Shin, J.; Bernard, M.; Yet, I.; Smart, M.; Gorrie-Stone, T.; Shaw, C.; Al Chalabi, A.; Ring, S. M.; Pershagen, G.; Melen, E.; Jimenez-Conde, J.; Roquer, J.; Lawlor, D. A.; Wright, J.; Martin, N. G.; Montgomery, G. W.; Moffitt, T. E.; Poulton, R.; Esko, T.; Milani, L.; Metspalu, A.; Perry, J. R. B.; Ong, K. K.; Wareham, N. J.; Matullo, G.; Sacerdote, C.; Panico, S.; Caspi, A.; Arseneault, L.; Gagnon, F.; Ollikainen, M.; Kaprio, J.; Felix, J. F.; Rivadeneira, F.; Tiemeier, H.; van IJzendoorn, M. H.; Uitterlinden, A. G.; Jaddoe, V. W. V.; Haley, C.; Mcintosh, A. M.; Evans, K. L.; Murray, A.; Raikkonen, K.; Lahti, J.; Nohr, E. A.; Sorensen, T. I. A.; Hansen, T.; Morgen, C. S.; Binder, E. B.; Lucae, S.; Gonzalez, J. R.; Bustamante, M.; Sunyer, J.; Holloway, J. W.; Karmaus, W.; Zhang, H.; Deary, I. J.; Wray, N. R.; Starr, J. M.; Beekman, M.; van Heemst, D.; Slagboom, P. E.; Morange, P. -E.; Tregouet, D. -A.; Veldink, J. H.; Davies, G. E.; de Geus, E. J. C.; Boomsma, D. I.; Vonk, J. M.; Brunekreef, B.; Koppelman, G. H.; Alarcon-Riquelme, M. E.; Huang, R. -C.; Pennell, C. E.; van Meurs, J.; Ikram, M. A.; Hughes, A. D.; Tillin, T.; Chaturvedi, N.; Pausova, Z.; Paus, T.; Spector, T. D.; Kumari, M.; Schalkwyk, L. C.; Visscher, P. M.; Davey Smith, G.; Bock, C.; Gaunt, T. R.; Bell, J. T.; Heijmans, B. T.; Mill, J.; Relton, C. L.

doi:10.1038/s41588-021-00923-x

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.