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

被引：250

作者：

Min, Josine L. ^{[1
,2
]}

Hemani, Gibran ^{[1
,2
]}

Hannon, Eilis ^{[3
]}

Dekkers, Koen F. ^{[4
]}

Castillo-Fernandez, Juan ^{[5
]}

Luijk, Rene ^{[4
]}

Carnero-Montoro, Elena ^{[5
,6
]}

Lawson, Daniel J. ^{[1
,2
]}

Burrows, Kimberley ^{[1
,2
]}

Suderman, Matthew ^{[1
,2
]}

Bretherick, Andrew D. ^{[7
]}

Richardson, Tom G. ^{[1
,2
]}

Klughammer, Johanna ^{[8
]}

Iotchkova, Valentina ^{[9
]}

Sharp, Gemma ^{[1
,2
]}

Al Khleifat, Ahmad ^{[10
]}

Shatunov, Aleksey ^{[10
]}

Iacoangeli, Alfredo ^{[10
,11
]}

McArdle, Wendy L. ^{[2
]}

Ho, Karen M. ^{[2
]}

Kumar, Ashish ^{[12
,13
,14
]}

Soderhall, Cilia ^{[15
]}

Soriano-Tarraga, Carolina ^{[16
]}

Giralt-Steinhauer, Eva ^{[16
]}

Kazmi, Nabila ^{[1
,2
]}

Mason, Dan ^{[17
]}

McRae, Allan F. ^{[18
]}

Corcoran, David L. ^{[19
]}

Sugden, Karen ^{[19
,20
]}

Kasela, Silva ^{[21
]}

Cardona, Alexia ^{[22
,23
]}

Day, Felix R. ^{[22
]}

Cugliari, Giovanni ^{[24
,25
]}

Viberti, Clara ^{[24
,25
]}

Guarrera, Simonetta ^{[24
,25
]}

Lerro, Michael ^{[26
]}

Gupta, Richa ^{[27
,28
]}

Bollepalli, Sailalitha ^{[27
,28
]}

Mandaviya, Pooja ^{[29
]}

Zeng, Yanni ^{[7
,30
,31
]}

Clarke, Toni-Kim ^{[32
]}

Walker, Rosie M. ^{[33
,34
]}

Schmoll, Vanessa ^{[35
]}

Czamara, Darina ^{[35
]}

Ruiz-Arenas, Carlos ^{[36
,37
,38
]}

Rezwan, Faisal, I ^{[39
]}

Marioni, Riccardo E. ^{[33
,34
]}

Lin, Tian ^{[18
]}

Awaloff, Yvonne ^{[35
]}

Germain, Marine ^{[40
]}

机构：

[1] Univ Bristol, MRC Integrat Epidemiol Unit, Bristol, Avon, England

[2] Univ Bristol, Bristol Med Sch, Populat Hlth Sci, Bristol, Avon, England

[3] Univ Exeter, Univ Exeter Med Sch, Coll Med & Hlth, Exeter, Devon, England

[4] Leiden Univ Med Ctr, Dept Biomed Data Sci, Mol Epidemiol, Leiden, Netherlands

[5] Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England

[6] Pfizer Univ Granada Andalusian Govt Ctr Genom & O, Granada, Spain

[7] Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland

[8] Austrian Acad Sci, CeMM Res Ctr Mol Med, Vienna, Austria

[9] MRC Weatherall Inst Mol Med, Oxford, England

[10] Maurice Wohl Clin Neurosci Inst, Dept Basic & Clin Neurosci, London, England

[11] Kings Coll London, Dept Biostat & Hlth Informat, London, England

[12] Karolinska Inst, Inst Environm Med, Stockholm, Sweden

[13] Swiss Trop & Publ Hlth Inst, Chron Dis Epidemiol Unit, Basel, Switzerland

[14] Univ Basel, Basel, Switzerland

[15] Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden

[16] Hosp Mar, Inst Hosp del Mar Invest Med, Neurol Dept, Barcelona, Spain

[17] Bradford Inst Hlth Res, Bradford, W Yorkshire, England

[18] Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia

[19] Duke Univ, Ctr Genom & Computat Biol, Durham, NC USA

[20] Duke Univ, Dept Psychol & Neurosci, Durham, NC USA

[21] Univ Tartu, Estonian Genome Ctr, Inst Genom, Tartu, Estonia

[22] Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England

[23] Univ Cambridge, Dept Genet, Cambridge, England

[24] Univ Turin, Dept Med Sci, Turin, Italy

[25] Italian Inst Genom Med, Turin, Italy

[26] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada

[27] Univ Helsinki, Inst Mol Med, Helsinki, Finland

[28] Univ Helsinki, Fac Med, Dept Publ Hlth, Helsinki, Finland

[29] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands

[30] Sun Yat Sen Univ, Fac Forens Med, Zhongshan Sch Med, Guangzhou, Peoples R China

[31] Sun Yat Sen Univ, Zhongshan Sch Med, Guangdong Prov Key Lab Brain Funct & Dis, Guangzhou, Peoples R China

[32] Univ Edinburgh, Royal Edinburgh Hosp, Div Psychiat, Edinburgh, Midlothian, Scotland

[33] Univ Edinburgh, Western Gen Hosp, Ctr Genom & Expt Med, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland

[34] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Dept Psychol, Edinburgh, Midlothian, Scotland

[35] Max Planck Inst Psychiat, Dept Translat Res Psychiat, Munich, Germany

[36] Barcelona Global Hlth Inst, ISGlobal, Barcelona, Spain

[37] Univ Pompeu Fabra, Barcelona, Spain

[38] CIBER Epidemiol & Salud Publ, Madrid, Spain

[39] Aberystwyth Univ, Dept Comp Sci, Aberystwyth, Dyfed, Wales

[40] Univ Bordeaux, Bordeaux Populat Hlth Ctr, INSERM UMR S 1219, Bordeaux, France

[41] Univ Heart Ctr Hamburg, Dept Gen & Intervent Cardiol, Hamburg, Germany

[42] Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Dept Neurol, Utrecht, Netherlands

[43] Vrije Univ Amsterdam, Amsterdam Publ Hlth Res Inst, Dept Biol Psychol, Amsterdam, Netherlands

[44] Univ Groningen, Univ Med Ctr Groningen, Beatrix Childrens Hosp, GRIAC Res Inst Groningen, Groningen, Netherlands

[45] Hannover Med Sch, CiiM, Hannover, Germany

[46] Hannover Med Sch, TWINCORE, Hannover, Germany

[47] Helmholtz Ctr Infect Res, Hannover, Germany

[48] Bellvitge Biomed Res Inst, Canc Epigenet & Biol Programme, Chromatin & Dis Grp, Barcelona, Spain

[49] CSIC, Inst Parasitol & Biomed Lopez Neyra, Granada, Spain

[50] Univ Newcastle, Coll Hlth Med & Wellbeing, Sch Med & Publ Hlth, Newcastle, NSW, Australia

来源：

NATURE GENETICS | 2021年 / 53卷 / 09期

基金：

英国生物技术与生命科学研究理事会; 英国经济与社会研究理事会; 英国惠康基金; 英国医学研究理事会;

关键词：

WIDE ASSOCIATION; MENDELIAN RANDOMIZATION; SNP ANALYSIS; COMPLEX; METAANALYSIS; VARIANTS; MODEL; LINKS; GWAS; EQTL;

D O I：

10.1038/s41588-021-00923-x

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

DNA methylation quantitative trait locus (mQTL) analyses on 32,851 participants identify genetic variants associated with DNA methylation at 420,509 sites in blood, resulting in a database of >270,000 independent mQTLs. 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.

引用

页码：1311 / +

页数：26

共 73 条

[1] Genetic effects on gene expression across human tissues [J].

Aguet, Francois ;

Brown, Andrew A. ;

Castel, Stephane E. ;

Davis, Joe R. ;

He, Yuan ;

Jo, Brian ;

Mohammadi, Pejman ;

Park, Yoson ;

Parsana, Princy ;

Segre, Ayellet V. ;

Strober, Benjamin J. ;

Zappala, Zachary ;

Cummings, Beryl B. ;

Gelfand, Ellen T. ;

Hadley, Kane ;

Huang, Katherine H. ;

Lek, Monkol ;

Li, Xiao ;

Nedzel, Jared L. ;

Nguyen, Duyen Y. ;

Noble, Michael S. ;

Sullivan, Timothy J. ;

Tukiainen, Taru ;

MacArthur, Daniel G. ;

Getz, Gad ;

Management, Nih Program ;

Addington, Anjene ;

Guan, Ping ;

Koester, Susan ;

Little, A. Roger ;

Lockhart, Nicole C. ;

Moore, Helen M. ;

Rao, Abhi ;

Struewing, Jeffery P. ;

Volpi, Simona ;

Collection, Biospecimen ;

Brigham, Lori E. ;

Hasz, Richard ;

Hunter, Marcus ;

Johns, Christopher ;

Johnson, Mark ;

Kopen, Gene ;

Leinweber, William F. ;

Lonsdale, John T. ;

McDonald, Alisa ;

Mestichelli, Bernadette ;

Myer, Kevin ;

Roe, Bryan ;

Salvatore, Michael ;

Shad, Saboor .

NATURE, 2017, 550 (7675) :204-+

[2] An integrated map of genetic variation from 1,092 human genomes [J].

Altshuler, David M. ;

Durbin, Richard M. ;

Abecasis, Goncalo R. ;

Bentley, David R. ;

Chakravarti, Aravinda ;

Clark, Andrew G. ;

Donnelly, Peter ;

Eichler, Evan E. ;

Flicek, Paul ;

Gabriel, Stacey B. ;

Gibbs, Richard A. ;

Green, Eric D. ;

Hurles, Matthew E. ;

Knoppers, Bartha M. ;

Korbel, Jan O. ;

Lander, Eric S. ;

Lee, Charles ;

Lehrach, Hans ;

Mardis, Elaine R. ;

Marth, Gabor T. ;

McVean, Gil A. ;

Nickerson, Deborah A. ;

Schmidt, Jeanette P. ;

Sherry, Stephen T. ;

Wang, Jun ;

Wilson, Richard K. ;

Gibbs, Richard A. ;

Dinh, Huyen ;

Kovar, Christie ;

Lee, Sandra ;

Lewis, Lora ;

Muzny, Donna ;

Reid, Jeff ;

Wang, Min ;

Wang, Jun ;

Fang, Xiaodong ;

Guo, Xiaosen ;

Jian, Min ;

Jiang, Hui ;

Jin, Xin ;

Li, Guoqing ;

Li, Jingxiang ;

Li, Yingrui ;

Li, Zhuo ;

Liu, Xiao ;

Lu, Yao ;

Ma, Xuedi ;

Su, Zhe ;

Tai, Shuaishuai ;

Tang, Meifang .

NATURE, 2012, 491 (7422) :56-65

[3] The Allelic Landscape of Human Blood Cell Trait Variation and Links to Common Complex Disease [J].

Astle, William J. ;

Elding, Heather ;

Jiang, Tao ;

Allen, Dave ;

Ruklisa, Dace ;

Mann, Alice L. ;

Mead, Daniel ;

Bouman, Heleen ;

Riveros-Mckay, Fernando ;

Kostadima, Myrto A. ;

Lambourne, John J. ;

Sivapalaratnam, Suthesh ;

Downes, Kate ;

Kundu, Kousik ;

Bomba, Lorenzo ;

Berentsen, Kim ;

Bradley, John R. ;

Daugherty, Louise C. ;

Delaneau, Olivier ;

Freson, Kathleen ;

Garner, Stephen F. ;

Grassi, Luigi ;

Guerrero, Jose ;

Haimel, Matthias ;

Janssen-Megens, Eva M. ;

Kaan, Anita ;

Kamat, Mihir ;

Kim, Bowon ;

Mandoli, Amit ;

Marchini, Jonathan ;

Martens, Joost H. A. ;

Meacham, Stuart ;

Megy, Karyn ;

O'Connell, Jared ;

Petersen, Romina ;

Sharifi, Nilofar ;

Sheard, Simon M. ;

Staley, James R. ;

Tuna, Salih ;

van der Ent, Martijn ;

Walter, Klaudia ;

Wang, Shuang-Yin ;

Wheeler, Eleanor ;

Wilder, Steven P. ;

Iotchkova, Valentina ;

Moore, Carmel ;

Sambrook, Jennifer ;

Stunnenberg, Hendrik G. ;

Di Angelantonio, Emanuele ;

Kaptoge, Stephen .

CELL, 2016, 167 (05) :1415-+

[4] Genomewide rapid association using mixed model and regression: A fast and simple method for genomewide pedigree-based quantitative trait loci association analysis [J].

Aulchenko, Yurii S. ;

de Koning, Dirk-Jan ;

Haley, Chris .

GENETICS, 2007, 177 (01) :577-585

[5] Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation [J].

Baubec, Tuncay ;

Colombo, Daniele F. ;

Wirbelauer, Christiane ;

Schmidt, Juliane ;

Burger, Lukas ;

Krebs, Arnaud R. ;

Akalin, Altuna ;

Schuebeler, Dirk .

NATURE, 2015, 520 (7546) :243-U278

[6] High density DNA methylation array with single CpG site resolution [J].

Bibikova, Marina ;

Barnes, Bret ;

Tsan, Chan ;

Ho, Vincent ;

Klotzle, Brandy ;

Le, Jennie M. ;

Delano, David ;

Zhang, Lu ;

Schroth, Gary P. ;

Gunderson, Kevin L. ;

Fan, Jian-Bing ;

Shen, Richard .

GENOMICS, 2011, 98 (04) :288-295

[7] Disease variants alter transcription factor levels and methylation of their binding sites [J].

Bonder, Marc Jan ;

Luijk, Rene ;

Zhernakova, Dania V. ;

Moed, Matthijs ;

Deelen, Patrick ;

Vermaat, Martijn ;

van Iterson, Maarten ;

van Dijk, Freerk ;

van Galen, Michiel ;

Bot, Jan ;

Slieker, Roderick C. ;

Jhamai, P. Mila ;

Verbiest, Michael ;

Suchiman, H. Eka D. ;

Verkerk, Marijn ;

van der Breggen, Ruud ;

van Rooij, Jeroen ;

Lakenberg, Nico ;

Arindrarto, Wibowo ;

Kielbasa, Szymon M. ;

Jonkers, Iris ;

van 't Hof, Peter ;

Nooren, Irene ;

Beekman, Marian ;

Deelen, Joris ;

van Heemst, Diana ;

Zhernakova, Alexandra ;

Tigchelaar, Ettje F. ;

Swertz, Morris A. ;

Hofman, Albert ;

Uitterlinden, Andre G. ;

Pool, Rene ;

van Dongen, Jenny ;

Hottenga, Jouke J. ;

Stehouwer, Coen D. A. ;

van der Kallen, Carla J. H. ;

Schalkwijk, Casper G. ;

van den Berg, Leonard H. ;

van Zwet, Erik W. ;

Mei, Hailiang ;

Li, Yang ;

Lemire, Mathieu ;

Hudson, Thomas J. ;

Slagboom, P. Eline ;

Wijmenga, Cisca ;

Veldink, Jan H. ;

van Greevenbroek, Marleen M. J. ;

van Duijn, Cornelia M. ;

Boomsma, Dorret I. ;

Isaacs, Aaron .

NATURE GENETICS, 2017, 49 (01) :131-138

[8] Epigenome-wide association study (EWAS) on lipids: the Rotterdam Study [J].

Braun, Kim V. E. ;

Dhana, Klodian ;

de Vries, Paul S. ;

Voortman, Trudy ;

van Meurs, Joyce B. J. ;

Uitterlinden, Andre G. ;

Hofman, Albert ;

Hu, Frank B. ;

Franco, Oscar H. ;

Dehghan, Abbas .

CLINICAL EPIGENETICS, 2017, 9

[9] Calculating statistical power in Mendelian randomization studies [J].

Brion, Marie-Jo A. ;

Shakhbazov, Konstantin ;

Visscher, Peter M. .

INTERNATIONAL JOURNAL OF EPIDEMIOLOGY, 2013, 42 (05) :1497-1501

[10] Second-generation PLINK: rising to the challenge of larger and richer datasets [J].

Chang, Christopher C. ;

Chow, Carson C. ;

Tellier, Laurent C. A. M. ;

Vattikuti, Shashaank ;

Purcell, Shaun M. ;

Lee, James J. .

GIGASCIENCE, 2015, 4

← 1 2 3 4 5 6 7 8 →