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

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 locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated...

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Detalles Bibliográficos
Autores principales: Min, Josine L, Hemani, Gibran, Hannon, Eilis, Dekkers, Koen F, Castillo-Fernandez, Juan, Luijk, René, Carnero-Montoro, Elena, Lawson, Daniel J, Burrows, Kimberley, Suderman, Matthew, Bretherick, Andrew D, Richardson, Tom G, Klughammer, Johanna, Iotchkova, Valentina, Sharp, Gemma, Al Khleifat, Ahmad, Shatunov, Aleksey, Iacoangeli, Alfredo, McArdle, Wendy L, Ho, Karen M, Kumar, Ashish, Söderhäll, Cilla, Soriano-Tárraga, Carolina, Giralt-Steinhauer, Eva, Kazmi, Nabila, Mason, Dan, McRae, Allan F, Corcoran, David L, Sugden, Karen, Kasela, Silva, Cardona, Alexia, Day, Felix R, Cugliari, Giovanni, Viberti, Clara, Guarrera, Simonetta, Lerro, Michael, Gupta, Richa, Bollepalli, Sailalitha, Mandaviya, Pooja, Zeng, Yanni, Clarke, Toni-Kim, Walker, Rosie M, Schmoll, Vanessa, Czamara, Darina, Ruiz-Arenas, Carlos, Rezwan, Faisal I, Marioni, Riccardo E, Lin, Tian, Awaloff, Yvonne, Germain, Marine, Aïssi, Dylan, Zwamborn, Ramona, van Eijk, Kristel, Dekker, Annelot, van Dongen, Jenny, Hottenga, Jouke-Jan, Willemsen, Gonneke, Xu, Cheng-Jian, Barturen, Guillermo, Català-Moll, Francesc, Kerick, Martin, Wang, Carol, Melton, Phillip, Elliott, Hannah R, Shin, Jean, Bernard, Manon, Yet, Idil, Smart, Melissa, Gorrie-Stone, Tyler, Shaw, Chris, Al Chalabi, Ammar, Ring, Susan M, Pershagen, Göran, Melén, Erik, Jiménez-Conde, Jordi, Roquer, Jaume, Lawlor, Deborah A, Wright, John, Martin, Nicholas G, Montgomery, Grant W, Moffitt, Terrie E, Poulton, Richie, Esko, Tõnu, Milani, Lili, Metspalu, Andres, Perry, John RB, Ong, Ken K, Wareham, Nicholas J, Matullo, Giuseppe, Sacerdote, Carlotta, Panico, Salvatore, Caspi, Avshalom, Arseneault, Louise, Gagnon, France, Ollikainen, Miina, Kaprio, Jaakko, Felix, Janine F, Rivadeneira, Fernando, Tiemeier, Henning, van IJzendoorn, Marinus H, Uitterlinden, André G, Jaddoe, Vincent WV, Haley, Chris, McIntosh, Andrew M, Evans, Kathryn L, Murray, Alison, Räikkönen, Katri, Lahti, Jari, Nohr, Ellen A, Sørensen, Thorkild IA, Hansen, Torben, Morgen, Camilla S, Binder, Elisabeth B, Lucae, Susanne, Gonzalez, Juan Ramon, Bustamante, Mariona, Sunyer, Jordi, Holloway, John W, Karmaus, Wilfried, Zhang, Hongmei, Deary, Ian J, Wray, Naomi R, Starr, John M, Beekman, Marian, van Heemst, Diana, Slagboom, P Eline, Morange, Pierre-Emmanuel, Trégouët, David-Alexandre, Veldink, Jan H, Davies, Gareth E, de Geus, Eco JC, Boomsma, Dorret I, Vonk, Judith M, Brunekreef, Bert, Koppelman, Gerard H, Alarcón-Riquelme, Marta E, Huang, Rae-Chi, Pennell, Craig E, van Meurs, Joyce, Ikram, M Arfan, Hughes, Alun D, Tillin, Therese, Chaturvedi, Nish, Pausova, Zdenka, Paus, Tomas, Spector, Timothy D, Kumari, Meena, Schalkwyk, Leonard C, Visscher, Peter M, Smith, George Davey, Bock, Christoph, Gaunt, Tom R, Bell, Jordana T, Heijmans, Bastiaan T, Mill, Jonathan, Relton, Caroline L
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2021
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7612069/
https://www.ncbi.nlm.nih.gov/pubmed/34493871
http://dx.doi.org/10.1038/s41588-021-00923-x
Descripción
Sumario: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 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 construct 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.

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