Variance component model to account for sample structure in genome-wide association studies
Hyun Min Kang,Jae Hoon Sul,Noah Zaitlen,Sit Yee Kong,Nelson B. Freimer,Chiara Sabatti,Eleazar Eskin +6 more
TLDR
A variance component approach implemented in publicly available software, EMMA eXpedited (EMMAX), that reduces the computational time for analyzing large GWAS data sets from years to hours is reported.Abstract:
Although genome-wide association studies (GWASs) have identified numerous loci associated with complex traits, imprecise modeling of the genetic relatedness within study samples may cause substantial inflation of test statistics and possibly spurious associations. Variance component approaches, such as efficient mixed-model association (EMMA), can correct for a wide range of sample structures by explicitly accounting for pairwise relatedness between individuals, using high-density markers to model the phenotype distribution; but such approaches are computationally impractical. We report here a variance component approach implemented in publicly available software, EMMA eXpedited (EMMAX), that reduces the computational time for analyzing large GWAS data sets from years to hours. We apply this method to two human GWAS data sets, performing association analysis for ten quantitative traits from the Northern Finland Birth Cohort and seven common diseases from the Wellcome Trust Case Control Consortium. We find that EMMAX outperforms both principal component analysis and genomic control in correcting for sample structure.read more
Citations
More filters
Journal ArticleDOI
LD score regression distinguishes confounding from polygenicity in genome-wide association studies :
Brendan Bulik-Sullivan,Po-Ru Loh,Hilary K. Finucane,Stephan Ripke,Jian Yang,Nick Patterson,Mark J. Daly,Alkes L. Price,Benjamin M. Neale +8 more
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.
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
Discovery and refinement of loci associated with lipid levels
Cristen J. Willer,Ellen M. Schmidt,Sebanti Sengupta,Gina M. Peloso,Gina M. Peloso,Gina M. Peloso,Stefan Gustafsson,Stavroula Kanoni,Andrea Ganna,Andrea Ganna,Jin Chen,Martin L. Buchkovich,Samia Mora,Jacques S. Beckmann,Jennifer L. Bragg-Gresham,Hsing-Yi Chang,Ayse Demirkan,Heleen M. den Hertog,Ron Do,Louise A. Donnelly,Georg Ehret,Georg Ehret,Tõnu Esko,Tõnu Esko,Mary F. Feitosa,Teresa Ferreira,Krista Fischer,Pierre Fontanillas,Ross M. Fraser,Daniel F. Freitag,Deepti Gurdasani,Deepti Gurdasani,Kauko Heikkilä,Elina Hyppönen,Aaron Isaacs,Anne U. Jackson,Åsa Johansson,Toby Johnson,Marika Kaakinen,Johannes Kettunen,Johannes Kettunen,Marcus E. Kleber,Marcus E. Kleber,Xiaohui Li,Jian'an Luan,Leo-Pekka Lyytikäinen,Patrik K. E. Magnusson,Massimo Mangino,Evelin Mihailov,May E. Montasser,Martina Müller-Nurasyid,Ilja M. Nolte,Jeffrey R. O'Connell,Cameron D. Palmer,Cameron D. Palmer,Markus Perola,Markus Perola,Markus Perola,Ann-Kristin Petersen,Serena Sanna,Richa Saxena,Sonia Shah,Dmitry Shungin,Dmitry Shungin,Carlo Sidore,Carlo Sidore,Ci Song,Ci Song,Rona J. Strawbridge,Ida Surakka,Ida Surakka,Toshiko Tanaka,Tanya M. Teslovich,Gudmar Thorleifsson,Evita G. Van Den Herik,Benjamin F. Voight,Kelly A. Volcik,Lindsay L. Waite,Andrew Wong,Ying Wu,Weihua Zhang,Weihua Zhang,Devin Absher,Gershim Asiki,Inês Barroso,Inês Barroso,Inês Barroso,Latonya F. Been,Jennifer L. Bolton,Lori L. Bonnycastle,Paolo Brambilla,Mary Susan Burnett,Giancarlo Cesana,Maria Dimitriou,Alex S. F. Doney,Angela Döring,Paul Elliott,Paul Elliott,Stephen E. Epstein,Gudmundur I. Eyjolfsson,Bruna Gigante,Mark O. Goodarzi,Harald Grallert,Martha L. Gravito,Christopher J. Groves,Göran Hallmans,Anna-Liisa Hartikainen,Caroline Hayward,Dena G. Hernandez,Andrew A. Hicks,Hilma Holm,Yi Jen Hung,Thomas Illig,Matthew Jones,Pontiano Kaleebu,John J.P. Kastelein,Kay-Tee Khaw,Eric Kim,Norman Klopp,Pirjo Komulainen,Meena Kumari,Claudia Langenberg,Terho Lehtimäki,Shih-Yi Lin,Jaana Lindström,Ruth J. F. Loos,Ruth J. F. Loos,François Mach,Wendy L. McArdle,Christa Meisinger,Braxton D. Mitchell,Gabrielle Müller,Ramaiah Nagaraja,Narisu Narisu,Tuomo Nieminen,Rebecca N. Nsubuga,Isleifur Olafsson,Ken K. Ong,Ken K. Ong,Aarno Palotie,Aarno Palotie,Theodore Papamarkou,Theodore Papamarkou,Theodore Papamarkou,Cristina Pomilla,Cristina Pomilla,Anneli Pouta,Anneli Pouta,Daniel J. Rader,Muredach P. Reilly,Paul M. Ridker,Fernando Rivadeneira,Igor Rudan,Aimo Ruokonen,Nilesh J. Samani,Nilesh J. Samani,Hubert Scharnagl,Janet Seeley,Janet Seeley,Kaisa Silander,Kaisa Silander,Alena Stančáková,Kathleen Stirrups,Amy J. Swift,Laurence Tiret,André G. Uitterlinden,L. Joost van Pelt,Sailaja Vedantam,Sailaja Vedantam,Nicholas W.J. Wainwright,Nicholas W.J. Wainwright,Cisca Wijmenga,Sarah H. Wild,Gonneke Willemsen,Tom Wilsgaard,James F. Wilson,Elizabeth H. Young,Elizabeth H. Young,Jing Hua Zhao,Linda S. Adair,Dominique Arveiler,Themistocles L. Assimes,Stefania Bandinelli,Franklyn I. Bennett,Murielle Bochud,Bernhard O. Boehm,Bernhard O. Boehm,Dorret I. Boomsma,Ingrid B. Borecki,Stefan R. Bornstein,Pascal Bovet,Michel Burnier,Harry Campbell,Aravinda Chakravarti,John C. Chambers,John C. Chambers,John C. Chambers,Yii-Der Ida Chen,Yii-Der Ida Chen,Francis S. Collins,Richard S. Cooper,John Danesh,George Dedoussis,Ulf de Faire,Alan B. Feranil,Jean Ferrières,Luigi Ferrucci,Nelson B. Freimer,Christian Gieger,Leif Groop,Leif Groop,Vilmundur Gudnason,Ulf Gyllensten,Anders Hamsten,Tamara B. Harris,Aroon D. Hingorani,Joel N. Hirschhorn,Joel N. Hirschhorn,Albert Hofman,G. Kees Hovingh,Chao A. Hsiung,Steve E. Humphries,Steven C. Hunt,Kristian Hveem,Carlos Iribarren,Marjo-Riitta Järvelin,Marjo-Riitta Järvelin,Marjo-Riitta Järvelin,Antti Jula,Mika Kähönen,Jaakko Kaprio,Jaakko Kaprio,Antero Kesäniemi,Mika Kivimäki,Jaspal S. Kooner,Jaspal S. Kooner,Jaspal S. Kooner,Peter J. Koudstaal,Ronald M. Krauss,Diana Kuh,Johanna Kuusisto,Kirsten Ohm Kyvik,Markku Laakso,Timo A. Lakka,Timo A. Lakka,Lars Lind,Cecilia M. Lindgren,Nicholas G. Martin,Winfried März,Winfried März,Winfried März,Mark I. McCarthy,Colin A. McKenzie,Pierre Meneton,Andres Metspalu,Leena Moilanen,Andrew D. Morris,Patricia B. Munroe,Inger Njølstad,Nancy L. Pedersen,Chris Power,Peter P. Pramstaller,Peter P. Pramstaller,Jackie F. Price,Bruce M. Psaty,Bruce M. Psaty,Thomas Quertermous,Rainer Rauramaa,Rainer Rauramaa,Danish Saleheen,Danish Saleheen,Veikko Salomaa,Dharambir K. Sanghera,Jouko Saramies,Peter Schwarz,Wayne Huey-Herng Sheu,Alan R. Shuldiner,Alan R. Shuldiner,Agneta Siegbahn,Tim D. Spector,Kari Stefansson,Kari Stefansson,David P. Strachan,Bamidele O. Tayo,Elena Tremoli,Jaakko Tuomilehto,Matti Uusitupa,Cornelia M. van Duijn,Peter Vollenweider,Lars Wallentin,Nicholas J. Wareham,John Whitfield,Bruce H. R. Wolffenbuttel,Jose M. Ordovas,Jose M. Ordovas,Eric Boerwinkle,Colin N. A. Palmer,Unnur Thorsteinsdottir,Unnur Thorsteinsdottir,Daniel I. Chasman,Jerome I. Rotter,Paul W. Franks,Paul W. Franks,Paul W. Franks,Samuli Ripatti,Samuli Ripatti,Samuli Ripatti,L. Adrienne Cupples,L. Adrienne Cupples,Manjinder S. Sandhu,Manjinder S. Sandhu,Stephen S. Rich,Michael Boehnke,Panos Deloukas,Sekar Kathiresan,Sekar Kathiresan,Karen L. Mohlke,Erik Ingelsson,Erik Ingelsson,Gonçalo R. Abecasis +319 more
TL;DR: It is found that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index.
Journal ArticleDOI
Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
Stephen Sawcer,Garrett Hellenthal,Matti Pirinen,Chris C. A. Spencer,Nikolaos A. Patsopoulos,Nikolaos A. Patsopoulos,Nikolaos A. Patsopoulos,Loukas Moutsianas,Alexander T. Dilthey,Zhan Su,Colin Freeman,Sarah E. Hunt,Sarah Edkins,Emma Gray,David R. Booth,Simon C. Potter,An Goris,Gavin Band,Annette Bang Oturai,A. Strange,Janna Saarela,Céline Bellenguez,Bertrand Fontaine,Matthew W. Gillman,Bernhard Hemmer,Rhian Gwilliam,Frauke Zipp,Alagurevathi Jayakumar,Roland Martin,Stephen Leslie,Stanley Hawkins,Eleni Giannoulatou,Sandra D'Alfonso,Hannah Blackburn,Filippo Martinelli Boneschi,Jennifer Liddle,Hanne F. Harbo,Hanne F. Harbo,M. Perez,Anne Spurkland,Matthew Waller,Marcin P. Mycko,Michelle Ricketts,Manuel Comabella,Naomi Hammond,Ingrid Kockum,O. T. McCann,Maria Ban,Pamela Whittaker,Anu Kemppinen,Paul A. Weston,Clive Hawkins,Sara Widaa,John Zajicek,John Zajicek,Serge Dronov,Neil Robertson,Suzannah Bumpstead,Lisa F. Barcellos,Lisa F. Barcellos,Rathi Ravindrarajah,Roby Abraham,Lars Alfredsson,Kristin G. Ardlie,Cristin Aubin,Amie Baker,K Baker,Sergio E. Baranzini,Laura Bergamaschi,Roberto Bergamaschi,Allan L. Bernstein,Achim Berthele,Mike Boggild,Jonathan P. Bradfield,David Brassat,Simon Broadley,Dorothea Buck,Helmut Butzkueven,Ruggero Capra,William M. Carroll,Paola Cavalla,Elisabeth Gulowsen Celius,Sabine Cepok,Rosetta M. Chiavacci,Françoise Clerget-Darpoux,Katleen Clysters,Giancarlo Comi,Mark D. Cossburn,Isabelle Cournu-Rebeix,M. B. Cox,Wendy Cozen,Bruce A.C. Cree,Anne H. Cross,Daniele Cusi,Mark J. Daly,Mark J. Daly,Emma J. Davis,Paul I.W. de Bakker,Paul I.W. de Bakker,Paul I.W. de Bakker,Marc Debouverie,Marie B. D'hooghe,K Dixon,Rita Dobosi,Bénédicte Dubois,David Ellinghaus,Irina Elovaara,Federica Esposito,Claire Fontenille,Simon J. Foote,Andre Franke,Daniela Galimberti,Angelo Ghezzi,Joseph T. Glessner,Refujia Gomez,Olivier Gout,Colin A. Graham,Struan F.A. Grant,Struan F.A. Grant,Franca Rosa Guerini,Hakon Hakonarson,Hakon Hakonarson,Per Hall,Anders Hamsten,Hans-Peter Hartung,Robert Heard,Simon Heath,Jeremy Hobart,Jeremy Hobart,Muna Hoshi,Carmen Infante-Duarte,Gillian Ingram,Wendy Ingram,Wendy Ingram,Talat Islam,Maja Jagodic,Michael Kabesch,Allan G. Kermode,Trevor J. Kilpatrick,Cecilia Kim,Norman Klopp,Keijo Koivisto,Malin Larsson,Mark Lathrop,Jeannette Lechner-Scott,Maurizio Leone,Virpi M. Leppä,Ulrika Liljedahl,Izaura Lima Bomfim,Robin R. Lincoln,Jenny Link,Jianjun Liu,Åslaug R. Lorentzen,Åslaug R. Lorentzen,Sara Lupoli,Fabio Macciardi,Fabio Macciardi,Thomas M. Mack,Mark Marriott,Vittorio Martinelli,Deborah F. Mason,Jacob L. McCauley,Frank D. Mentch,Inger-Lise Mero,Tania Mihalova,Xavier Montalban,John Mottershead,Kjell-Morten Myhr,Paola Naldi,William E R Ollier,Alison Page,Aarno Palotie,Jean Pelletier,Laura Piccio,Trevor Pickersgill,Fredrik Piehl,Susan Pobywajlo,Hong L. Quach,Patricia P. Ramsay,Mauri Reunanen,Richard Reynolds,John D. Rioux,John D. Rioux,Mariaemma Rodegher,Sabine Roesner,Justin P. Rubio,Ina-Maria Rueckert,Marco Salvetti,Erika Salvi,Adam Santaniello,Catherine Schaefer,Stefan Schreiber,Christian Schulze,Rodney J. Scott,Finn Sellebjerg,Krzysztof Selmaj,David Sexton,Ling Shen,Brigid Simms-Acuna,Sheila Skidmore,Patrick M. A. Sleiman,C. Smestad,Per Soelberg Sørensen,Helle Bach Søndergaard,Jim Stankovich,Richard C. Strange,Anna-Maija Sulonen,Emilie Sundqvist,Ann-Christine Syvaenen,Francesca Taddeo,Bruce V. Taylor,Jenefer M. Blackwell,Jenefer M. Blackwell,Jenefer M. Blackwell,Pentti J. Tienari,Elvira Bramon,Ayman Tourbah,Matthew A. Brown,Ewa Tronczynska,Juan P. Casas,Niall Tubridy,Aiden Corvin,Jane Vickery,Jane Vickery,Janusz Jankowski,Pablo Villoslada,Hugh S. Markus,Kai Wang,Christopher G. Mathew,James Wason,Colin N. A. Palmer,H-Erich Wichmann,H-Erich Wichmann,Robert Plomin,Ernest Willoughby,Anna Rautanen,Juliane Winkelmann,Michael Wittig,Richard C. Trembath,J. Yaouanq,Ananth C. Viswanathan,Ananth C. Viswanathan,Haitao Zhang,Nicholas W. Wood,Rebecca L. Zuvich,Panos Deloukas,Cordelia Langford,Audrey Duncanson,Jorge R. Oksenberg,Margaret A. Pericak-Vance,Jonathan L. Haines,Tomas Olsson,Jan Hillert,Adrian J. Ivinson,Philip L. De Jager,Philip L. De Jager,Philip L. De Jager,Leena Peltonen,Graeme J. Stewart,David A. Hafler,David A. Hafler,Stephen L. Hauser,Gil McVean,Peter Donnelly,Peter Donnelly,Alastair Compston +265 more
TL;DR: In this article, a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, they have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci.
Journal ArticleDOI
Genome-wide efficient mixed-model analysis for association studies.
Xiang Zhou,Matthew Stephens +1 more
TL;DR: This method is approximately n times faster than the widely used exact method known as efficient mixed-model association (EMMA), where n is the sample size, making exact genome-wide association analysis computationally practical for large numbers of individuals.
References
More filters
Book
Introduction to quantitative genetics
TL;DR: The genetic constitution of a population: Hardy-Weinberg equilibrium and changes in gene frequency: migration mutation, changes of variance, and heritability are studied.
Journal ArticleDOI
Categorical Data Analysis
TL;DR: In this article, categorical data analysis was used for categorical classification of categorical categorical datasets.Categorical Data Analysis, categorical Data analysis, CDA, CPDA, CDSA
Journal ArticleDOI
Principal components analysis corrects for stratification in genome-wide association studies
Alkes L. Price,Alkes L. Price,Nick Patterson,Robert M. Plenge,Robert M. Plenge,Michael E. Weinblatt,Nancy A. Shadick,David Reich,David Reich +8 more
TL;DR: This work describes a method that enables explicit detection and correction of population stratification on a genome-wide scale and uses principal components analysis to explicitly model ancestry differences between cases and controls.
Journal ArticleDOI
Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls
Paul Burton,David Clayton,Lon R. Cardon,Nicholas John Craddock,Panos Deloukas,Audrey Duncanson,Dominic P. Kwiatkowski,Mark I. McCarthy,Willem H. Ouwehand,Nilesh J. Samani,John A. Todd,Peter Donnelly,Jeffrey C. Barrett,Dan Davison,Doug Easton,David M. Evans,H. T. Leung,Jonathan Marchini,Andrew P. Morris,Chris C. A. Spencer,Martin D. Tobin,Antony P. Attwood,James P. Boorman,Barbara Cant,Ursula Everson,Judith M. Hussey,Jennifer Jolley,Alexandra S. Knight,Kerstin Koch,Elizabeth Meech,Sarah Nutland,Christopher Prowse,Helen Stevens,Niall C. Taylor,Graham R. Walters,Neil Walker,Nicholas A. Watkins,Thilo Winzer,Richard Jones,Wendy L. McArdle,Susan M. Ring,David P. Strachan,Marcus Pembrey,Gerome Breen,David St Clair,Sian Caesar,Katherine Gordon-Smith,Lisa Jones,Christine Fraser,Elaine K. Green,Detelina Grozeva,Marian L. Hamshere,Peter Holmans,Ian Jones,George Kirov,Valentina Moskvina,Ivan Nikolov,Michael Conlon O'Donovan,Michael John Owen,David A. Collier,Amanda Elkin,Anne Farmer,Richard Williamson,Peter McGuffin,Allan H. Young,I. Nicol Ferrier,Stephen G. Ball,Anthony J. Balmforth,Jennifer H. Barrett,D. Timothy Bishop,Mark M. Iles,Azhar Maqbool,Nadira Yuldasheva,Alistair S. Hall,Peter S. Braund,Richard J. Dixon,Massimo Mangino,Suzanne Stevens,John R. Thompson,Francesca Bredin,Mark Tremelling,Miles Parkes,Hazel E. Drummond,Charlie W. Lees,Elaine R. Nimmo,Jack Satsangi,Sheila A. Fisher,Alastair Forbes,Cathryn M. Lewis,Clive M. Onnie,Natalie J. Prescott,Jeremy D. Sanderson,Christopher G. Mathew,Jamie Barbour,M. Khalid Mohiuddin,Catherine E. Todhunter,John C. Mansfield,Tariq Ahmad,Fraser Cummings,Derek P. Jewell,John Webster,Morris J. Brown,G. Mark Lathrop,John M. C. Connell,Anna F. Dominiczak,Carolina A. Braga Marcano,Beverley Burke,Richard Dobson,Johannie Gungadoo,Kate L. Lee,Patricia B. Munroe,Stephen Newhouse,Abiodun Onipinla,Chris Wallace,Mingzhan Xue,Mark J. Caulfield,Martin Farrall,Anne Barton,Ian N. Bruce,Hannah Donovan,Steve Eyre,Paul D. Gilbert,Samantha L. Hider,Anne Hinks,Sally John,Catherine Potter,Alan J. Silman,Deborah P M Symmons,Wendy Thomson,Jane Worthington,David B. Dunger,Barry Widmer,Timothy M. Frayling,Rachel M. Freathy,Hana Lango,John R. B. Perry,Beverley M. Shields,Michael N. Weedon,Andrew T. Hattersley,Graham A. Hitman,Mark Walker,Kate S. Elliott,Christopher J. Groves,Cecilia M. Lindgren,Nigel W. Rayner,Nicholas J. Timpson,Eleftheria Zeggini,Melanie J. Newport,Giorgio Sirugo,Emily J. Lyons,Fredrik O. Vannberg,Adrian V. S. Hill,Linda A. Bradbury,C Farrar,J J Pointon,Paul Wordsworth,Matthew A. Brown,Jayne A. Franklyn,Joanne M. Heward,Matthew J. Simmonds,Stephen C. L. Gough,Sheila Seal,Michael R. Stratton,Nazneen Rahman,Maria Ban,An Goris,Stephen Sawcer,Alastair Compston,David J. Conway,Muminatou Jallow,Kirk A. Rockett,Suzannah Bumpstead,Amy Chaney,Kate Downes,Mohammed J. R. Ghori,Rhian Gwilliam,Sarah E. Hunt,Michael Inouye,Andrew Keniry,Emma King,Ralph McGinnis,Simon C. Potter,Rathi Ravindrarajah,Pamela Whittaker,Claire Widden,David Withers,Niall Cardin,Teresa Ferreira,Joanne Pereira-Gale,Ingileif B. Hallgrímsdóttir,Bryan Howie,Zhan Su,Yik Ying Teo,Damjan Vukcevic,David Bentley,A Compston +195 more
TL;DR: This study has demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in theBritish population is generally modest.
Journal ArticleDOI
Finding the missing heritability of complex diseases
Teri A. Manolio,Francis S. Collins,Nancy J. Cox,David Goldstein,Lucia A. Hindorff,David J. Hunter,Mark I. McCarthy,Erin M. Ramos,Lon R. Cardon,Aravinda Chakravarti,Judy H. Cho,Alan E. Guttmacher,Augustine Kong,Leonid Kruglyak,Leonid Kruglyak,Elaine R. Mardis,Charles N. Rotimi,Montgomery Slatkin,David Valle,Alice S. Whittemore,Michael Boehnke,Andrew G. Clark,Evan E. Eichler,Greg Gibson,Jonathan L. Haines,Trudy F. C. Mackay,Steven A. McCarroll,Peter M. Visscher +27 more
TL;DR: This paper examined potential sources of missing heritability and proposed research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.