Predicting causal variants affecting expression by using whole-genome sequencing and RNA-seq from multiple human tissues

Nature Genetics
Andrew A BrownEmmanouil T Dermitzakis


Genetic association mapping produces statistical links between phenotypes and genomic regions, but identifying causal variants remains difficult. Whole-genome sequencing (WGS) can help by providing complete knowledge of all genetic variants, but it is financially prohibitive for well-powered GWAS studies. We performed mapping of expression quantitative trait loci (eQTLs) with WGS and RNA-seq, and found that lead eQTL variants called with WGS were more likely to be causal. Through simulations, we derived properties of causal variants and used them to develop a method for identifying likely causal SNPs. We estimated that 25-70% of causal variants were located in open-chromatin regions, depending on the tissue and experiment. Finally, we identified a set of high-confidence causal variants and showed that these were more enriched in GWAS associations than other eQTLs. Of those, we found 65 associations with GWAS traits and provide examples in which genes implicated by expression are functionally validated as being relevant for complex traits.


Jan 11, 2000·Nucleic Acids Research·S T SherryK Sirotkin
Mar 10, 2001·Nature·Eric S LanderInternational Human Genome Sequencing Consortium
Jul 29, 2003·Proceedings of the National Academy of Sciences of the United States of America·John D Storey, Robert Tibshirani
Aug 7, 2007·PLoS Genetics·Bertrand Servin, Matthew Stephens
Oct 9, 2009·Nature·Teri ManolioPeter M Visscher
Nov 17, 2009·Obesity·David JelinekWilliam S Garver
May 4, 2010·Biological Psychiatry·Diego A Pizzagalli
Jun 3, 2010·Nature Reviews. Genetics·Jonathan L Marchini, Bryan Howie
Nov 3, 2010·Human Molecular Genetics·David JelinekWilliam S Garver
Sep 4, 2012·Nature Genetics·Elin GrundbergMultiple Tissue Human Expression Resource (MuTHER) Consortium
Sep 8, 2012·Genome Research·Jennifer HarrowTim J Hubbard
Oct 30, 2012·Nature Methods·Santiago Marco-SolaPaolo Ribeca
Jan 31, 2013·BMC Endocrine Disorders·Clara BambaceAgné Kulyté
May 15, 2013·PLoS Genetics·Timothée FlutreMatthew Stephens
Sep 17, 2013·Nature·Tuuli LappalainenEmmanouil T Dermitzakis
Oct 1, 2013·Nature Genetics·International Multiple Sclerosis Genetics Consortium (IMSGC)Jacob L McCauley
Oct 8, 2013·Nature Genetics·Cristen J WillerGlobal Lipids Genetics Consortium
Dec 10, 2013·Nucleic Acids Research·Danielle WelterHelen Parkinson
Jul 25, 2014·Nature·Schizophrenia Working Group of the Psychiatric Genomics Consortium
Aug 12, 2014·Genetics·Farhad HormozdiariEleazar Eskin
Sep 17, 2014·Nature Communications·Nicholas J TimpsonUK1OK Consortium Members
Dec 2, 2014·Nature Genetics·Alfonso BuilEmmanouil T Dermitzakis
Feb 13, 2015·Nature·Adam E LockeElizabeth K Speliotes
Feb 20, 2015·Nature·Roadmap Epigenomics ConsortiumManolis Kellis
Apr 24, 2015·PLoS Genetics·Xiaoquan WenRoger Pique-Regi
Jul 11, 2015·Human Molecular Genetics·Sarah L Spain, Jeffrey C Barrett
Sep 15, 2015·Nature·UK10K ConsortiumNicole Soranzo
Oct 4, 2015·Nature·1000 Genomes Project ConsortiumGoncalo Abecasis
Dec 29, 2015·Bioinformatics·Halit OngenOlivier Delaneau
May 31, 2016·American Journal of Human Genetics·Xiaoquan WenRoger Pique-Regi
Jul 12, 2016·Nature·Christian FuchsbergerMark I McCarthy
Oct 28, 2016·Nature Neuroscience·Menachem FromerPamela Sklar
Sep 30, 2016·Nature·Momoko HorikoshiRachel M Freathy
Nov 22, 2016·American Journal of Human Genetics·Farhad HormozdiariEleazar Eskin
May 19, 2017·Nature Communications·Olivier DelaneauEmmanouil T Dermitzakis
Oct 24, 2017·Nature Genetics·Halit OngenEmmanouil T Dermitzakis


Apr 15, 2018·Circulation. Genomic and Precision Medicine·Kiran MusunuruXiao-Zhong James Luo
Jan 27, 2019·Genes·Alina S UstiugovaAnd Marina A Afanasyeva
Apr 23, 2019·PLoS Genetics·Vitor R C AguiarDiogo Meyer
Nov 22, 2018·Frontiers in Cardiovascular Medicine·Maria F HughesHelen M Roche
Nov 15, 2019·The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences·Jamison McCorrisonNicholas J Schork
Oct 15, 2019·PeerJ·Siliang ChenYuehong Zheng
Oct 21, 2020·Scientific Reports·Sebastian Carrasco ProJuan Ignacio Fuxman Bass
Nov 3, 2020·Bioinformatics·Li LiuGreg Gibson
Jan 20, 2021·Genetics, Selection, Evolution : GSE·Zehu YuanHans D Daetwyler
Jan 22, 2021·Cell Systems·Jeffrey Molendijk, Benjamin L Parker
Feb 28, 2021·Nature Communications·Julia SteinbergEleftheria Zeggini
Apr 16, 2020·Trends in Genetics : TIG·Youqiong YeLeng Han
Mar 4, 2021·Forensic Science International. Genetics·Cordula HaasJack Ballantyne

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