Journal ArticleDOI
Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets
Zhihong Zhu,Futao Zhang,Han Hu,Andrew Bakshi,Matthew R. Robinson,Joseph E. Powell,Grant W. Montgomery,Michael E. Goddard,Naomi R. Wray,Peter M. Visscher,Jian Yang +10 more
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TLDR
A method is proposed that integrates summary-level data from GWAS with data from expression quantitative trait locus (eQTL) studies to identify genes whose expression levels are associated with a complex trait because of pleiotropy, and prioritize 126 genes that provide important leads to design future functional studies.Abstract:
Genome-wide association studies (GWAS) have identified thousands of genetic variants associated with human complex traits. However, the genes or functional DNA elements through which these variants exert their effects on the traits are often unknown. We propose a method (called SMR) that integrates summary-level data from GWAS with data from expression quantitative trait locus (eQTL) studies to identify genes whose expression levels are associated with a complex trait because of pleiotropy. We apply the method to five human complex traits using GWAS data on up to 339,224 individuals and eQTL data on 5,311 individuals, and we prioritize 126 genes (for example, TRAF1 and ANKRD55 for rheumatoid arthritis and SNX19 and NMRAL1 for schizophrenia), of which 25 genes are new candidates; 77 genes are not the nearest annotated gene to the top associated GWAS SNP. These genes provide important leads to design future functional studies to understand the mechanism whereby DNA variation leads to complex trait variation.read more
Citations
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Journal ArticleDOI
Genetic effects on gene expression across human tissues.
Enhancing GTEx (eGTEx) groups,Nih Common Fund,Nhgri,Biospecimen Core Resource—VARI,Elsi study,Genome Browser Data Integration Visualization—EBI,Lead analysts,Alexis Battle,Christopher D. Brown,Barbara E. Engelhardt,Stephen B. Montgomery +10 more
TL;DR: It is found that local genetic variation affects gene expression levels for the majority of genes, and inter-chromosomal genetic effects for 93 genes and 112 loci are identified, enabling a mechanistic interpretation of gene regulation and the genetic basis of disease.
Journal ArticleDOI
10 Years of GWAS Discovery: Biology, Function, and Translation
Peter M. Visscher,Naomi R. Wray,Qian Zhang,Pamela Sklar,Mark I. McCarthy,Matthew A. Brown,Jian Yang +6 more
TL;DR: The remarkable range of discoveriesGWASs has facilitated in population and complex-trait genetics, the biology of diseases, and translation toward new therapeutics are reviewed.
Journal ArticleDOI
The MR-Base platform supports systematic causal inference across the human phenome
Gibran Hemani,Jie Zheng,Benjamin Elsworth,Kaitlin H Wade,Valeriia Haberland,Denis Baird,Charles Laurin,Stephen Burgess,Jack Bowden,Ryan Langdon,Vanessa Y Tan,James Yarmolinsky,Hashem A Shihab,Nicholas J. Timpson,David M. Evans,David M. Evans,Caroline L Relton,Richard M. Martin,George Davey Smith,Tom R. Gaunt,Philip C Haycock +20 more
TL;DR: MR-Base is a platform that integrates a curated database of complete GWAS results (no restrictions according to statistical significance) with an application programming interface, web app and R packages that automate 2SMR, and includes several sensitivity analyses for assessing the impact of horizontal pleiotropy and other violations of assumptions.
Journal ArticleDOI
Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression
Naomi R. Wray,Stephan Ripke,Stephan Ripke,Stephan Ripke,Manuel Mattheisen,Maciej Trzaskowski,Enda M. Byrne,Abdel Abdellaoui,Mark Adams,Esben Agerbo,Esben Agerbo,Tracy Air,Till M.F. Andlauer,Silviu Alin Bacanu,Marie Bækvad-Hansen,Marie Bækvad-Hansen,Aartjan F.T. Beekman,Tim B. Bigdeli,Elisabeth B. Binder,Elisabeth B. Binder,Douglas Blackwood,Julien Bryois,Henriette N. Buttenschøn,Henriette N. Buttenschøn,Jonas Bybjerg-Grauholm,Jonas Bybjerg-Grauholm,Na Cai,Na Cai,Enrique Castelao,Jane H. Christensen,Jane H. Christensen,Toni-Kim Clarke,Jonathan I.R. Coleman,Lucía Colodro-Conde,Baptiste Couvy-Duchesne,Nicholas John Craddock,Gregory E. Crawford,Cheynna A. Crowley,Hassan S. Dashti,Hassan S. Dashti,Gail Davies,Ian J. Deary,Franziska Degenhardt,Eske M. Derks,Nese Direk,Nese Direk,Conor V. Dolan,Erin C. Dunn,Erin C. Dunn,Thalia C. Eley,Nicholas Eriksson,Valentina Escott-Price,Farnush Hassan Farhadi Kiadeh,Hilary K. Finucane,Hilary K. Finucane,Andreas J. Forstner,Josef Frank,Helena Gaspar,Michael Gill,Paola Giusti-Rodríguez,Fernando S. Goes,Scott D. Gordon,Jakob Grove,Lynsey S. Hall,Lynsey S. Hall,Eilis Hannon,Christine Søholm Hansen,Christine Søholm Hansen,Thomas Hansen,Thomas Hansen,Stefan Herms,Stefan Herms,Ian B. Hickie,Per Hoffmann,Per Hoffmann,Georg Homuth,Carsten Horn,Jouke-Jan Hottenga,David M. Hougaard,David M. Hougaard,Ming Hu,Craig L. Hyde,Marcus Ising,Rick Jansen,Fulai Jin,Eric Jorgenson,James A. Knowles,Isaac S. Kohane,Isaac S. Kohane,Isaac S. Kohane,Julia Kraft,Warren W. Kretzschmar,Jesper Krogh,Zoltán Kutalik,Zoltán Kutalik,Jacqueline M. Lane,Jacqueline M. Lane,Yihan Li,Yun Li,Penelope A. Lind,Xiaoxiao Liu,Leina Lu,Donald J. MacIntyre,Dean F. MacKinnon,Robert Maier,Wolfgang Maier,Jonathan Marchini,Hamdi Mbarek,Patrick J. McGrath,Peter McGuffin,Sarah E. Medland,Divya Mehta,Divya Mehta,Christel M. Middeldorp,Christel M. Middeldorp,Evelin Mihailov,Yuri Milaneschi,Lili Milani,Jonathan Mill,Francis M. Mondimore,Grant W. Montgomery,Sara Mostafavi,Niamh Mullins,Matthias Nauck,Bernard Ng,Michel G. Nivard,Dale R. Nyholt,Paul F. O'Reilly,Hogni Oskarsson,Michael John Owen,Jodie N. Painter,Carsten Bøcker Pedersen,Carsten Bøcker Pedersen,Marianne Giørtz Pedersen,Marianne Giørtz Pedersen,Roseann E. Peterson,Erik Pettersson,Wouter J. Peyrot,Giorgio Pistis,Danielle Posthuma,Shaun Purcell,Jorge A. Quiroz,Per Qvist,Per Qvist,John P. Rice,Brien P. Riley,Margarita Rivera,Margarita Rivera,Saira Saeed Mirza,Richa Saxena,Richa Saxena,Robert A. Schoevers,Eva C. Schulte,Ling Shen,Jianxin Shi,Stanley I. Shyn,Engilbert Sigurdsson,Grant Sinnamon,Johannes H. Smit,Daniel J. Smith,Hreinn Stefansson,Stacy Steinberg,Craig A. Stockmeier,Fabian Streit,Jana Strohmaier,Katherine E. Tansey,Henning Teismann,Alexander Teumer,Wesley K. Thompson,Pippa A. Thomson,Thorgeir E. Thorgeirsson,Chao Tian,Matthew Traylor,Jens Treutlein,Vassily Trubetskoy,André G. Uitterlinden,Daniel Umbricht,Sandra Van der Auwera,Albert M. van Hemert,Alexander Viktorin,Peter M. Visscher,Yunpeng Wang,Yunpeng Wang,Yunpeng Wang,Bradley T. Webb,Shantel Weinsheimer,Shantel Weinsheimer,Jürgen Wellmann,Gonneke Willemsen,Stephanie H. Witt,Yang Wu,Hualin S. Xi,Jian Yang,Futao Zhang,Volker Arolt,Bernhard T. Baune,Klaus Berger,Dorret I. Boomsma,Sven Cichon,Udo Dannlowski,E. C.J. De Geus,J. Raymond DePaulo,Enrico Domenici,Katharina Domschke,Tõnu Esko,Tõnu Esko,Hans J. Grabe,Steven P. Hamilton,Caroline Hayward,Andrew C. Heath,David A. Hinds,Kenneth S. Kendler,Stefan Kloiber,Stefan Kloiber,Stefan Kloiber,Glyn Lewis,Qingqin S. Li,Susanne Lucae,Pamela F.A. Madden,Patrik K. E. Magnusson,Nicholas G. Martin,Andrew M. McIntosh,Andres Metspalu,Ole Mors,Ole Mors,Preben Bo Mortensen,Bertram Müller-Myhsok,Bertram Müller-Myhsok,Merete Nordentoft,Merete Nordentoft,Markus M. Nöthen,Michael Conlon O'Donovan,Sara A. Paciga,Nancy L. Pedersen,Brenda W.J.H. Penninx,Roy H. Perlis,David J. Porteous,James B. Potash,Martin Preisig,Marcella Rietschel,Catherine Schaefer,Thomas G. Schulze,Jordan W. Smoller,Jordan W. Smoller,Kari Stefansson,Kari Stefansson,Henning Tiemeier,Rudolf Uher,Henry Völzke,Myrna M. Weissman,Myrna M. Weissman,Thomas Werge,Thomas Werge,Thomas Werge,Ashley R. Winslow,Ashley R. Winslow,Cathryn M. Lewis,Douglas F. Levinson,Gerome Breen,Anders D. Børglum,Anders D. Børglum,Patrick F. Sullivan,Patrick F. Sullivan +262 more
TL;DR: A genome-wide association meta-analysis of individuals with clinically assessed or self-reported depression identifies 44 independent and significant loci and finds important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia.
References
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Gonçalo R. Abecasis,David Altshuler,David Altshuler,Adam Auton,Lisa D Brooks,Richard Durbin,Richard A. Gibbs,Matthew E. Hurles,Gil McVean +8 more
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Gejman,Michael Gill,Hugh Gurling,Christina M. Hultman,Nakao Iwata,Assen Jablensky,Erik G. Jönsson,Erik G. Jönsson,Kenneth S. Kendler,George Kirov,Jo Knight,Todd Lencz,Todd Lencz,Douglas F. Levinson,Qingqin S. Li,Jianjun Liu,Jianjun Liu,Anil K. Malhotra,Anil K. Malhotra,Steven A. McCarroll,Steven A. McCarroll,Andrew McQuillin,Jennifer L. Moran,Preben Bo Mortensen,Preben Bo Mortensen,Bryan J. Mowry,Markus M. Noethen,Roel A. Ophoff,Roel A. Ophoff,Michael John Owen,Aarno Palotie,Aarno Palotie,Aarno Palotie,Carlos N. Pato,Tracey L. Petryshen,Tracey L. Petryshen,Danielle Posthuma,Danielle Posthuma,Marcella Rietschel,Brien P. Riley,Dan Rujescu,Dan Rujescu,Pak C. Sham,Pamela Sklar,David St Clair,Daniel R. Weinberger,Jens R. Wendland,Thomas Werge,Thomas Werge,Mark J. Daly,Mark J. Daly,Patrick F. Sullivan,Patrick F. Sullivan,Michael Conlon O'Donovan +354 more
TL;DR: Associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses.
Journal ArticleDOI
The International HapMap Project
John W. Belmont,Paul Hardenbol,Thomas D. Willis,Fuli Yu,Huanming Yang,Lan Yang Ch'Ang,Wei Huang,Bin Liu,Yan Shen,Paul K.H. Tam,Lap-Chee Tsui,Mary M.Y. Waye,Jeffrey Tze Fei Wong,Changqing Zeng,Qingrun Zhang,Mark S. Chee,Luana Galver,Semyon Kruglyak,Sarah S. Murray,Arnold Oliphant,Alexandre Montpetit,Fanny Chagnon,Vincent Ferretti,Martin Leboeuf,Michael S. Phillips,Andrei Verner,Shenghui Duan,Denise L. Lind,Raymond D. Miller,John P. Rice,Nancy L. Saccone,Patricia Taillon-Miller,Ming Xiao,Akihiro Sekine,Koki Sorimachi,Yoichi Tanaka,Tatsuhiko Tsunoda,Eiji Yoshino,David R. Bentley,Sarah E. Hunt,Don Powell,Houcan Zhang,Ichiro Matsuda,Yoshimitsu Fukushima,Darryl Macer,Eiko Suda,Charles N. Rotimi,Clement Adebamowo,Toyin Aniagwu,Patricia A. Marshall,Olayemi Matthew,Chibuzor Nkwodimmah,Charmaine D.M. Royal,Mark Leppert,Missy Dixon,Fiona Cunningham,Ardavan Kanani,Gudmundur A. Thorisson,Peter E. Chen,David J. Cutler,Carl S. Kashuk,Peter Donnelly,Jonathan Marchini,Gilean McVean,Simon Myers,Lon R. Cardon,Andrew P. Morris,Bruce S. Weir,James C. Mullikin,Michael Feolo,Mark J. Daly,Renzong Qiu,Alastair Kent,Georgia M. Dunston,Kazuto Kato,Norio Niikawa,Jessica Watkin,Richard A. Gibbs,Erica Sodergren,George M. Weinstock,Richard K. Wilson,Lucinda Fulton,Jane Rogers,Bruce W. Birren,Hua Han,Hongguang Wang,Martin Godbout,John C. Wallenburg,Paul L'Archevêque,Guy Bellemare,Kazuo Todani,Takashi Fujita,Satoshi Tanaka,Arthur L. Holden,Francis S. Collins,Lisa D. Brooks,Jean E. McEwen,Mark S. Guyer,Elke Jordan,Jane Peterson,Jack Spiegel,Lawrence M. Sung,Lynn F. Zacharia,Karen Kennedy,Michael Dunn,Richard Seabrook,Mark Shillito,Barbara Skene,John Stewart,David Valle,Ellen Wright Clayton,Lynn B. Jorde,Aravinda Chakravarti,Mildred K. Cho,Troy Duster,Troy Duster,Morris W. Foster,Maria Jasperse,Bartha Maria Knoppers,Pui-Yan Kwok,Julio Licinio,Jeffrey C. Long,Pilar N. Ossorio,Vivian Ota Wang,Charles N. Rotimi,Patricia Spallone,Patricia Spallone,Sharon F. Terry,Eric S. Lander,Eric H. Lai,Deborah A. Nickerson,Gonçalo R. Abecasis,David Altshuler,Michael Boehnke,Panos Deloukas,Julie A. Douglas,Stacey Gabriel,Richard R. Hudson,Thomas J. Hudson,Leonid Kruglyak,Yusuke Nakamura,Robert L. Nussbaum,Stephen F. Schaffner,Stephen T. Sherry,Lincoln Stein,Toshihiro Tanaka +145 more
TL;DR: The HapMap will allow the discovery of sequence variants that affect common disease, will facilitate development of diagnostic tools, and will enhance the ability to choose targets for therapeutic intervention.
Journal ArticleDOI
GCTA: a tool for genome-wide complex trait analysis.
TL;DR: The GCTA software is a versatile tool to estimate and partition complex trait variation with large GWAS data sets and focuses on the function of estimating the variance explained by all the SNPs on the X chromosome and testing the hypotheses of dosage compensation.
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