Systematic Mendelian randomization framework elucidates hundreds of CpG sites which may mediate the influence of genetic variants on disease

被引:42
作者
Richardson, Tom G. [1 ]
Haycock, Philip C. [1 ]
Zheng, Jie [1 ]
Timpson, Nicholas J. [1 ]
Gaunt, Tom R. [1 ]
Smith, George Davey [1 ]
Relton, Caroline L. [1 ]
Hemani, Gibran [1 ]
机构
[1] Univ Bristol, Bristol Med Sch Populat Hlth Sci, MRC Integrat Epidemiol Unit IEU, Oakfield House, Bristol BS8 2BN, Avon, England
基金
英国医学研究理事会; 英国生物技术与生命科学研究理事会; 英国惠康基金;
关键词
EPIGENOME-WIDE ASSOCIATION; BODY-MASS INDEX; DNA METHYLATION; GENOME; TISSUE; IDENTIFICATION; EXPRESSION; RISK; METAANALYSIS; STATISTICS;
D O I
10.1093/hmg/ddy210
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
We have undertaken a systematic Mendelian randomization (MR) study using methylation quantitative trait loci (meQTL) as genetic instruments to assess the relationship between genetic variation, DNA methylation and 139 complex traits. Using two-sample MR, we identified 1148 associations across 61 traits where genetic variants were associated with both proximal DNA methylation (i.e. cis-meQTL) and complex trait variation (P < 1.39 x 10(-08)). Joint likelihood mapping provided evidence that the genetic variant which influenced DNA methylation levels for 348 of these associations across 47 traits was also responsible for variation in complex traits. These associations showed a high rate of replication in the BIOS QTL and UK Biobank datasets for 14 selected traits, as 101 of the attempted 128 associations survived multiple testing corrections (P < 3.91 x 10(-04)). Integrating expression quantitative trait loci (eQTL) data suggested that genetic variants responsible for 306 of the 348 refined meQTL associations also influence gene expression, which indicates a coordinated system of effects that are consistent with causality. CpG sites were enriched for histone mark peaks in tissue types relevant to their associated trait and implicated genes were enriched across relevant biological pathways. Though we are unable to distinguish mediation from horizontal pleiotropy in these analyses, our findings should prove valuable in prioritizing candidate loci where DNA methylation may influence traits and help develop mechanistic insight into the aetiology of complex disease.
引用
收藏
页码:3293 / 3304
页数:12
相关论文
共 66 条
[1]  
[Anonymous], 2017, BIORXIV
[2]   The ChEMBL bioactivity database: an update [J].
Bento, A. Patricia ;
Gaulton, Anna ;
Hersey, Anne ;
Bellis, Louisa J. ;
Chambers, Jon ;
Davies, Mark ;
Krueger, Felix A. ;
Light, Yvonne ;
Mak, Lora ;
McGlinchey, Shaun ;
Nowotka, Michal ;
Papadatos, George ;
Santos, Rita ;
Overington, John P. .
NUCLEIC ACIDS RESEARCH, 2014, 42 (D1) :D1083-D1090
[3]   Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project [J].
Birney, Ewan ;
Stamatoyannopoulos, John A. ;
Dutta, Anindya ;
Guigo, Roderic ;
Gingeras, Thomas R. ;
Margulies, Elliott H. ;
Weng, Zhiping ;
Snyder, Michael ;
Dermitzakis, Emmanouil T. ;
Stamatoyannopoulos, John A. ;
Thurman, Robert E. ;
Kuehn, Michael S. ;
Taylor, Christopher M. ;
Neph, Shane ;
Koch, Christoph M. ;
Asthana, Saurabh ;
Malhotra, Ankit ;
Adzhubei, Ivan ;
Greenbaum, Jason A. ;
Andrews, Robert M. ;
Flicek, Paul ;
Boyle, Patrick J. ;
Cao, Hua ;
Carter, Nigel P. ;
Clelland, Gayle K. ;
Davis, Sean ;
Day, Nathan ;
Dhami, Pawandeep ;
Dillon, Shane C. ;
Dorschner, Michael O. ;
Fiegler, Heike ;
Giresi, Paul G. ;
Goldy, Jeff ;
Hawrylycz, Michael ;
Haydock, Andrew ;
Humbert, Richard ;
James, Keith D. ;
Johnson, Brett E. ;
Johnson, Ericka M. ;
Frum, Tristan T. ;
Rosenzweig, Elizabeth R. ;
Karnani, Neerja ;
Lee, Kirsten ;
Lefebvre, Gregory C. ;
Navas, Patrick A. ;
Neri, Fidencio ;
Parker, Stephen C. J. ;
Sabo, Peter J. ;
Sandstrom, Richard ;
Shafer, Anthony .
NATURE, 2007, 447 (7146) :799-816
[4]   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
[5]   Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator [J].
Bowden, Jack ;
Smith, George Davey ;
Haycock, Philip C. ;
Burgess, Stephen .
GENETIC EPIDEMIOLOGY, 2016, 40 (04) :304-314
[6]   Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression [J].
Bowden, Jack ;
Smith, George Davey ;
Burgess, Stephen .
INTERNATIONAL JOURNAL OF EPIDEMIOLOGY, 2015, 44 (02) :512-525
[7]   Cohort Profile: The 'Children of the 90s'-the index offspring of the Avon Longitudinal Study of Parents and Children [J].
Boyd, Andy ;
Golding, Jean ;
Macleod, John ;
Lawlor, Debbie A. ;
Fraser, Abigail ;
Henderson, John ;
Molloy, Lynn ;
Ness, Andy ;
Ring, Susan ;
Smith, George Davey .
INTERNATIONAL JOURNAL OF EPIDEMIOLOGY, 2013, 42 (01) :111-127
[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]   Using published data in Mendelian randomization: a blueprint for efficient identification of causal risk factors [J].
Burgess, Stephen ;
Scott, Robert A. ;
Timpson, Nicholas J. ;
Smith, George Davey ;
Thompson, Simon G. .
EUROPEAN JOURNAL OF EPIDEMIOLOGY, 2015, 30 (07) :543-552
[10]   Mendelian Randomization Analysis With Multiple Genetic Variants Using Summarized Data [J].
Burgess, Stephen ;
Butterworth, Adam ;
Thompson, Simon G. .
GENETIC EPIDEMIOLOGY, 2013, 37 (07) :658-665