Integrative approaches for large-scale transcriptome-wide association studies.
Alexander Gusev,Alexander Gusev,Arthur Ko,Huwenbo Shi,Gaurav Bhatia,Gaurav Bhatia,Wonil Chung,Brenda W.J.H. Penninx,Rick Jansen,Eco J. C. de Geus,Dorret I. Boomsma,Fred A. Wright,Patrick F. Sullivan,Patrick F. Sullivan,Elina Nikkola,Marcus Alvarez,Mete Civelek,Aldons J. Lusis,Terho Lehtimäki,Emma Raitoharju,Mika Kähönen,Ilkka Seppälä,Olli T. Raitakari,Olli T. Raitakari,Johanna Kuusisto,Markku Laakso,Alkes L. Price,Alkes L. Price,Päivi Pajukanta,Bogdan Pasaniuc +29 more
TLDR
A powerful strategy that integrates gene expression measurements with summary association statistics from large-scale genome-wide association studies (GWAS) to identify genes whose cis-regulated expression is associated with complex traits is introduced.Abstract:
Many genetic variants influence complex traits by modulating gene expression, thus altering the abundance of one or multiple proteins. Here we introduce a powerful strategy that integrates gene expression measurements with summary association statistics from large-scale genome-wide association studies (GWAS) to identify genes whose cis-regulated expression is associated with complex traits. We leverage expression imputation from genetic data to perform a transcriptome-wide association study (TWAS) to identify significant expression-trait associations. We applied our approaches to expression data from blood and adipose tissue measured in ∼ 3,000 individuals overall. We imputed gene expression into GWAS data from over 900,000 phenotype measurements to identify 69 new genes significantly associated with obesity-related traits (BMI, lipids and height). Many of these genes are associated with relevant phenotypes in the Hybrid Mouse Diversity Panel. Our results showcase the power of integrating genotype, gene expression and phenotype to gain insights into the genetic basis of complex traits.read more
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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.
Hundreds of variants clustered in genomic loci and biological pathways affect human height
Hana Lango Allen,Karol Estrada,Guillaume Lettre,Sonja I. Berndt,Michael N. Weedon,Fernando Rivadeneira,Cristen J. Willer,Anne U. Jackson,Sailaja Vedantam,Soumya Raychaudhuri,Teresa Ferreira,Andrew R. Wood,Robert J. Weyant,Ayellet V. Segrè,Elizabeth K. Speliotes,Eleanor Wheeler,Nicole Soranzo,Ju-Hyun Park,Jian Yang,Daniel F. Gudbjartsson,Nancy L. Heard-Costa,Joshua C. Randall,Lu Qi,Albert V. Smith,Reedik Maegi,Tomi Pastinen,Liming Liang,Iris M. Heid,Jian'an Luan,Gudmar Thorleifsson,Thomas W. Winkler,Michael E. Goddard,Ken Sin Lo,Cameron D. Palmer,Tsegaselassie Workalemahu,Yurii S. Aulchenko,Åsa Johansson,M. Carola Zillikens,Mary F. Feitosa,Tõnu Esko,Toby Johnson,Shamika Ketkar,Peter Kraft,Massimo Mangino,Inga Prokopenko,Devin Absher,Eva Albrecht,Florian Ernst,Nicole L. Glazer,Caroline Hayward,Jouke-Jan Hottenga,Kevin B. Jacobs,Joshua W. Knowles,Zoltán Kutalik,Keri L. Monda,Ozren Polasek,Michael Preuss,Nigel W. Rayner,Neil R. Robertson,Valgerdur Steinthorsdottir,Jonathan Tyrer,Benjamin F. Voight,Fredrik Wiklund,Jianfeng Xu,Jing Hua Zhao,Dale R. Nyholt,Niina Pellikka,Markus Perola,John R. B. Perry,Ida Surakka,Mari-Liis Tammesoo,Elizabeth L. Altmaier,Najaf Amin,Thor Aspelund,Tushar Bhangale,Gabrielle Boucher,Daniel I. Chasman,Constance Chen,Lachlan J. M. Coin,Mark E. Cooper,Anna L. Dixon,Quince Gibson,Elin Grundberg,Ke Hao,M. Juhani Junttila,Lee M. Kaplan,Johannes Kettunen,Inke R. Koenig,Tony Kwan,Robert Lawrence,Douglas F. Levinson,Mattias Lorentzon,Barbara McKnight,Andrew P. Morris,Martina Mueller,Julius S. Ngwa,Shaun Purcell,Suzanne Rafelt,Rany M. Salem,Erika Salvi,Serena Sanna,Jianxin Shi,Ulla Sovio,John R. Thompson,Michael C. Turchin,Liesbeth Vandenput,Dominique J. Verlaan,Veronique Vitart,Charles C. White,Andreas Ziegler,Peter Almgren,Anthony J. Balmforth,Harry Campbell,Lorena Citterio,Alessandro De Grandi,Anna F. Dominiczak,Jubao Duan,Paul Elliott,Roberto Elosua,Johan G. Eriksson,Nelson B. Freimer,Eco J. C. de Geus,Nicola Glorioso,Shen Haiqing,Anna-Liisa Hartikainen,Aki S. Havulinna,Andrew A. Hicks,Jennie Hui,Wilmar Igl,Thomas Illig,Antti Jula,Eero Kajantie,Tuomas O. Kilpelaeinen,Markku Koiranen,Ivana Kolcic,Seppo Koskinen,Peter Kovacs,Jaana Laitinen,Jianjun Liu,Marja-Liisa Lokki,Ana Marušić,Andrea Maschio,Thomas Meitinger,Antonella Mulas,Guillaume Paré,Alex N. Parker,John F. Peden,Astrid Petersmann,Irene Pichler,Kirsi H. Pietiläinen,Anneli Pouta,Martin Riddertrale,Jerome I. Rotter,Jennifer G. Sambrook,Alan R. Sanders,Carsten Oliver Schmidt,Juha Sinisalo,Jan Smit,Heather M. Stringham,G. Bragi Walters,Elisabeth Widen,Sarah H. Wild,Gonneke Willemsen,Laura Zagato,Lina Zgaga,Paavo Zitting,Helene Alavere,Martin Farrall,Wendy L. McArdle,Mari Nelis,Marjolein Peters,Samuli Ripatti,Joyce B. J. vVan Meurs,Katja K.H. Aben,Kristin G. Ardlie,Jacques S. Beckmann,John Beilby,Richard N. Bergman,Sven Bergmann,Francis S. Collins,Daniele Cusi,Martin den Heijer,Gudny Eiriksdottir,Pablo V. Gejman,Alistair S. Hall,Anders Hamsten,Heikki V. Huikuri,Carlos Iribarren,Mika Kähönen,Jaakko Kaprio,Sekar Kathiresan,Lambertus A. Kiemeney,Thomas D. Kocher,Lenore J. Launer,Terho Lehtimäki,Olle Melander,Thomas H. Mosley,Arthur W. Musk,Markku S. Nieminen,Christopher J. O'Donnell,Claes Ohlsson,Ben A. Oostra,Lyle J. Palmer,Olli T. Raitakari,Paul M. Ridker,John D. Rioux,Aila Rissanen,Carlo Rivolta,Heribert Schunkert,Alan R. Shuldiner,David S. Siscovick,Michael Stumvoll,Anke Toenjes,Jaakko Tuomilehto,Gert-Jan B. van Ommen,Jorma Viikari,Andrew C. Heath,Nicholas G. Martin,Grant W. Montgomery,Michael A. Province,Manfred Kayser,Alice M. Arnold,Larry D. Atwood,Eric Boerwinkle,Stephen J. Chanock,Panos Deloukas,Christian Gieger,Henrik Grönberg,Per Hall,Andrew T. Hattersley,Christian Hengstenberg,Wolfgang Hoffman,G. Mark Lathrop,Veikko Salomaa,Stefan Schreiber,Manuela Uda,Dawn M. Waterworth,Alan F. Wright,Themistocles L. Assimes,Inês Barroso,Albert Hofman,Karen L. Mohlke,Dorret I. Boomsma,Mark J. Caulfield,L. Adrienne Cupples,Jeanette Erdmann,Caroline S. Fox,Vilmundur Gudnason,Ulf Gyllensten,Tamara B. Harris,Richard B. Hayes,Marjo-Ritta Jarvelin,Vincent Mooser,Patricia B. Munroe,Willem H. Ouwehand,Brenda W.J.H. Penninx,Peter P. Pramstaller,Thomas Quertermous,Igor Rudan,Nilesh J. Samani,Tim D. Spector,Henry Voelzke,Hugh Watkins,James F. Wilson,Leif Groop,Talin Haritunians,Frank B. Hu,Robert C. Kaplan,Andres Metspalu,Kari E. North,David Schlessinger,Nicholas J. Wareham,David J. Hunter,Jeffrey R. O'Connell,David P. Strachan,H. Erich Schadt,Unnur Thorsteinsdottir,Leena Peltonen,André G. Uitterlinden,Peter M. Visscher,Nilanjan Chatterjee,Ruth J. F. Loos,Michael Boehnke,Mark I. McCarthy,Erik Ingelsson,Cecilia M. Lindgren,Gonçalo R. Abecasis,Kari Stefansson,Timothy M. Frayling,Joel N. Hirschhorn +289 more
TL;DR: In this paper, the authors show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait, revealing patterns with important implications for genetic studies of common human diseases and traits.
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
TL;DR: 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.
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Journal ArticleDOI
LD score regression distinguishes confounding from polygenicity in genome-wide association studies :
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TL;DR: It is found that polygenicity accounts for the majority of the inflation in test statistics in many GWAS of large sample size, and the LD Score regression intercept can be used to estimate a more powerful and accurate correction factor than genomic control.
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Welch,Mary Kate Wing,Xiaowei Zhan,Philip Awadalla,Philip Awadalla,Alan Hodgkinson,Yun Li,Xinghua Shi,Andrew Quitadamo,Gerton Lunter,Jonathan Marchini,Simon Myers,Claire Churchhouse,Olivier Delaneau,Olivier Delaneau,Anjali Gupta-Hinch,Warren W. Kretzschmar,Zamin Iqbal,Iain Mathieson,Androniki Menelaou,Androniki Menelaou,Andy Rimmer,Dionysia Kiara Xifara,Taras K. Oleksyk,Yunxin Fu,Xiaoming Liu,Momiao Xiong,Lynn B. Jorde,David J. Witherspoon,Jinchuan Xing,Brian L. Browning,Sharon R. Browning,Fereydoun Hormozdiari,Peter H. Sudmant,Ekta Khurana,Chris Tyler-Smith,Cornelis A. Albers,Qasim Ayub,Yuan Chen,Vincenza Colonna,Vincenza Colonna,Luke Jostins,Klaudia Walter,Yali Xue,Mark Gerstein,Alexej Abyzov,Suganthi Balasubramanian,Jieming Chen,Declan Clarke,Yao Fu,Arif Harmanci,Mike Jin,Dong-Hoon Lee,Jeremy Liu,Xinmeng Jasmine Mu,Xinmeng Jasmine Mu,Jing Zhang,Yan Zhang,Christopher Hartl,Khalid Shakir,Jeremiah D. 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Henn,Danielle Jones,Jane Kaye,Alastair Kent,Angeliki Kerasidou,Rasika A. Mathias,Pilar N. Ossorio,Michael Parker,Charles N. Rotimi,Charmaine D.M. Royal,Karla Sandoval,Yeyang Su,Zhongming Tian,Sarah A. Tishkoff,Marc Via,Yuhong Wang,Huanming Yang,Ling Yang,Jiayong Zhu,Walter F. Bodmer,Gabriel Bedoya,Zhiming Cai,Yang Gao,Jiayou Chu,Leena Peltonen,Andrés C. García-Montero,Alberto Orfao,Julie Dutil,Juan Carlos Martínez-Cruzado,R. Mathias,Anselm Hennis,Harold Watson,Colin A. McKenzie,Firdausi Qadri,Regina C. LaRocque,Xiaoyan Deng,Danny Asogun,Onikepe A. Folarin,Christian T. Happi,Omonwunmi Omoniwa,Matt Stremlau,Matt Stremlau,Ridhi Tariyal,Ridhi Tariyal,M Jallow,M Jallow,Fatoumatta Sisay Joof,Fatoumatta Sisay Joof,Tumani Corrah,Tumani Corrah,Kirk A. Rockett,Kirk A. Rockett,Dominic P. Kwiatkowski,Dominic P. Kwiatkowski,Jaspal S. Kooner,Tran Tinh Hien,Sarah J. Dunstan,Sarah J. Dunstan,Nguyen ThuyHang,Richard Fonnie,Robert F. Garry,Lansana Kanneh,Lina M. Moses,John S. Schieffelin,Donald S. Grant,Carla Gallo,Giovanni Poletti,Danish Saleheen,Asif Rasheed,Lisa D. Brooks,Adam Felsenfeld,Jean E. McEwen,Yekaterina Vaydylevich,Audrey Duncanson,Michael Dunn,Jeffery A. Schloss +517 more