A General Approach for Haplotype Phasing across the Full Spectrum of Relatedness
Jared O'Connell,Deepti Gurdasani,Olivier Delaneau,Nicola Pirastu,Sheila Ulivi,Massimiliano Cocca,Michela Traglia,Jie Huang,Jennifer E. Huffman,Igor Rudan,Ruth McQuillan,Ross M. Fraser,Harry Campbell,Ozren Polasek,Gershim Asiki,Kenneth Ekoru,Caroline Hayward,Alan F. Wright,Veronique Vitart,Pau Navarro,Jean-François Zagury,James F. Wilson,Daniela Toniolo,Paolo Gasparini,Nicole Soranzo,Manjinder S. Sandhu,Jonathan Marchini +26 more
TLDR
It is found that SHAPEIT2 produces much lower switch error rates in all cohorts compared to other methods, including those designed specifically for isolated populations, and a general strategy for phasing cohorts with any level of implicit or explicit relatedness between individuals is developed.Abstract:
Many existing cohorts contain a range of relatedness between genotyped individuals, either by design or by chance. Haplotype estimation in such cohorts is a central step in many downstream analyses. Using genotypes from six cohorts from isolated populations and two cohorts from non-isolated populations, we have investigated the performance of different phasing methods designed for nominally ‘unrelated’ individuals. We find that SHAPEIT2 produces much lower switch error rates in all cohorts compared to other methods, including those designed specifically for isolated populations. In particular, when large amounts of IBD sharing is present, SHAPEIT2 infers close to perfect haplotypes. Based on these results we have developed a general strategy for phasing cohorts with any level of implicit or explicit relatedness between individuals. First SHAPEIT2 is run ignoring all explicit family information. We then apply a novel HMM method (duoHMM) to combine the SHAPEIT2 haplotypes with any family information to infer the inheritance pattern of each meiosis at all sites across each chromosome. This allows the correction of switch errors, detection of recombination events and genotyping errors. We show that the method detects numbers of recombination events that align very well with expectations based on genetic maps, and that it infers far fewer spurious recombination events than Merlin. The method can also detect genotyping errors and infer recombination events in otherwise uninformative families, such as trios and duos. The detected recombination events can be used in association scans for recombination phenotypes. The method provides a simple and unified approach to haplotype estimation, that will be of interest to researchers in the fields of human, animal and plant genetics.read more
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A global reference for human genetic variation.
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TL;DR: The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations, and has reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-generation sequencing, deep exome sequencing, and dense microarray genotyping.
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.
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Human Demographic History Impacts Genetic Risk Prediction across Diverse Populations
Alicia R. Martin,Christopher R. Gignoux,Raymond K. Walters,Genevieve L. Wojcik,Benjamin M. Neale,Benjamin M. Neale,Simon Gravel,Mark J. Daly,Mark J. Daly,Carlos Bustamante,Eimear E. Kenny +10 more
TL;DR: It is demonstrated that scores inferred from European GWASs are biased by genetic drift in other populations even when choosing the same causal variants and that biases in any direction are possible and unpredictable.
Journal ArticleDOI
Association analysis identifies 65 new breast cancer risk loci
Kyriaki Michailidou,Kyriaki Michailidou,Sara Lindström,Sara Lindström,Joe Dennis,Jonathan Beesley,Shirley Hui,Siddhartha Kar,Audrey Lemaçon,Penny Soucy,Dylan M. Glubb,Asha Rostamianfar,Manjeet K. Bolla,Qin Wang,Jonathan Tyrer,Ed Dicks,Andy C. H. Lee,Zhaoming Wang,Jamie Allen,Renske Keeman,Ursula Eilber,Juliet D. French,Xiaoqing Chen,Laura Fachal,Karen McCue,Amy E. McCart Reed,Maya Ghoussaini,Jason S. Carroll,Xia Jiang,Hilary K. Finucane,Hilary K. Finucane,Marcia Adams,Muriel A. Adank,Habibul Ahsan,Kristiina Aittomäki,Hoda Anton-Culver,Natalia Antonenkova,Volker Arndt,Kristan J. Aronson,Banu Arun,Paul L. Auer,Paul L. Auer,Francois Bacot,Myrto Barrdahl,Caroline Baynes,Matthias W. Beckmann,Sabine Behrens,Javier Benitez,Marina Bermisheva,Leslie Bernstein,Carl Blomqvist,Natalia Bogdanova,Stig E. Bojesen,Stig E. Bojesen,Bernardo Bonanni,Anne Lise Børresen-Dale,Judith S. Brand,Hiltrud Brauch,Hiltrud Brauch,Hiltrud Brauch,Paul Brennan,Hermann Brenner,Louise A. Brinton,Per Broberg,Ian W. 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Nordestgaard,Børge G. Nordestgaard,Aaron D. Norman,Olufunmilayo I. Olopade,Janet E. Olson,Håkan Olsson,Curtis Olswold,Nick Orr,V. Shane Pankratz,Sue K. Park,Sue K. Park,Tjoung-Won Park-Simon,Rachel Lloyd,Jose Ignacio Arias Perez,Paolo Peterlongo,Julian Peto,Kelly-Anne Phillips,Mila Pinchev,Dijana Plaseska-Karanfilska,Ross L. Prentice,Nadege Presneau,Darya Prokofyeva,Elizabeth W. Pugh,Katri Pylkäs,Brigitte Rack,Paolo Radice,Nazneen Rahman,Gadi Rennert,Hedy S. Rennert,Valerie Rhenius,Atocha Romero,Jane Romm,Kathryn J. Ruddy,Thomas Rüdiger,Anja Rudolph,Matthias Ruebner,Emiel J. Th. Rutgers,Emmanouil Saloustros,Dale P. Sandler,Suleeporn Sangrajrang,Elinor J. Sawyer,Daniel F. Schmidt,Rita K. Schmutzler,Andreas Schneeweiss,Minouk J. Schoemaker,Fredrick R. Schumacher,Peter Schürmann,Rodney J. Scott,Rodney J. Scott,Christopher G. Scott,Sheila Seal,Caroline Seynaeve,Mitul Shah,Priyanka Sharma,Chen-Yang Shen,Chen-Yang Shen,Grace Sheng,Mark E. Sherman,Martha J. 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TL;DR: A genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry finds that heritability of Breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2–5-fold enriched relative to the genome- wide average.
Journal ArticleDOI
Gene expression elucidates functional impact of polygenic risk for schizophrenia
Menachem Fromer,Panos Roussos,Solveig K. Sieberts,Jessica S. Johnson,David H. Kavanagh,Thanneer M. Perumal,Douglas M. Ruderfer,Edwin C. Oh,Aaron Topol,Hardik Shah,Lambertus Klei,Robin Kramer,Dalila Pinto,Zeynep H. Gümüş,A. Ercument Cicek,Kristen K. Dang,Andrew W. Browne,Cong Lu,Lu Xie,Ben Readhead,Eli A. Stahl,Jianqiu Xiao,Mahsa Parvisi,Tymor Hamamsy,John F. Fullard,Ying-Chih Wang,Milind Mahajan,Jonathan M. J. Derry,Joel T. Dudley,Scott E. Hemby,Benjamin A. Logsdon,Konrad Talbot,Towfique Raj,Towfique Raj,David A. Bennett,Philip L. De Jager,Philip L. De Jager,Jun Zhu,Bin Zhang,Patrick F. Sullivan,Patrick F. Sullivan,Andrew Chess,Shaun Purcell,Leslie A. Shinobu,Lara M. Mangravite,Hiroyoshi Toyoshiba,Raquel E. Gur,Chang-Gyu Hahn,David A. Lewis,Vahram Haroutunian,Mette A. Peters,Barbara K. Lipska,Joseph D. Buxbaum,Eric E. Schadt,Keisuke Hirai,Kathryn Roeder,Kristen J. Brennand,Nicholas Katsanis,Enrico Domenici,Bernie Devlin,Pamela Sklar +60 more
TL;DR: It is shown that schizophrenia is polygenic and the utility of this resource of gene expression and its genetic regulation for mechanistic interpretations of genetic liability for brain diseases is highlighted.
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Journal ArticleDOI
A haplotype map of the human genome
John W. Belmont,Andrew Boudreau,Suzanne M. Leal,Paul Hardenbol,Shiran Pasternak,David A. Wheeler,Thomas D. Willis,Fuli Yu,Huanming Yang,Gao Yang,H. B. Hu,Weitao Hu,Chaohua Li,Wei Lin,Siqi Liu,Hao Pan,Xiaoli Tang,Jian Wang,Wei Wang,Jun Yu,Bo Zhang,Qingrun Zhang,Hongbin Zhao,Jun Zhou,Rachel Barry,Brendan Blumenstiel,Amy L. Camargo,Matthew Defelice,Maura Faggart,Mary Goyette,Supriya Gupta,Jamie Moore,Huy Nguyen,Melissa Parkin,Jessica Roy,Erich Stahl,Ellen Winchester,David Altshuler,Yan Shen,Zhijian Yao,Wei Huang,Xun Chu,Yungang He,Li Jin,Yangfan Liu,Yayun Shen,Weiwei Sun,Haifeng Wang,Yi Wang,Ying Wang,Xiaoyan Xiong,Liang Xu,Mary M.Y. Waye,Stephen Kwok-Wing Tsui,Hong Xue,J. Tze Fei Wong,Launa M. Galver,Jian-Bing Fan,Sarah S. Murray,Arnold Oliphant,Mark S. Chee,Alexandre Montpetit,Fanny Chagnon,Vincent Ferretti,Martin Leboeuf,Jean François Olivier,Michael S. Phillips,Stéphanie Roumy,Clémentine Sallée,Andrei Verner,Thomas J. Hudson,Kelly A. Frazer,Dennis G. Ballinger,David R. Cox,David A. Hinds,Laura L. Stuve,Pui-Yan Kwok,Dongmei Cai,Daniel C. Koboldt,Raymond D. Miller,Ludmila Pawlikowska,Patricia Taillon-Miller,Ming Xiao,Lap-Chee Tsui,William Mak,Pak C. Sham,You-Qiang Song,Paul K.H. Tam,Yusuke Nakamura,Takahisa Kawaguchi,Takuya Kitamoto,Takashi Morizono,Atsushi Nagashima,Yozo Ohnishi,Akihiro Sekine,Toshihiro Tanaka,Panos Deloukas,Christine P. Bird,Marcos Delgado,Emmanouil T. Dermitzakis,Rhian Gwilliam,Sarah E. Hunt,Jonathan Morrison,Don Powell,Barbara E. Stranger,Pamela Whittaker,David R. Bentley,Paul I.W. de Bakker,Jeffrey C. Barrett,Ben Fry,Julian Maller,Steve McCarroll,Nick Patterson,Itsik Pe'er,Shaun Purcell,Daniel J. Richter,Pardis C. Sabeti,Richa Saxena,Stephen F. Schaffner,Patrick Varilly,Lincoln Stein,Lalitha Krishnan,Albert V. Smith,Gudmundur A. Thorisson,Aravinda Chakravarti,Peter E. Chen,David J. Cutler,Carl S. Kashuk,Shin Lin,Gonçalo R. Abecasis,Weihua Guan,Heather M. Munro,Zhaohui S. Qin,Daryl J. Thomas,Gilean McVean,Leonardo Bottolo,Susana Eyheramendy,Colin Freeman,Jonathan Marchini,Simon Myers,Chris C. A. Spencer,Matthew Stephens,Peter Donnelly,Lon R. Cardon,Geraldine M. Clarke,David M. Evans,Andrew P. Morris,Bruce S. Weir,Tatsuhiko Tsunoda,James C. Mullikin,Stephen T. Sherry,Michael Feolo,Houcan Zhang,Changqing Zeng,Hui Zhao,Ichiro Matsuda,Yoshimitsu Fukushima,Darryl Macer,Eiko Suda,Charles N. Rotimi,Clement Adebamowo,Ike Ajayi,Toyin Aniagwu,Patricia A. Marshall,Chibuzor Nkwodimmah,Charmaine D.M. Royal,Mark Leppert,Missy Dixon,Andy Peiffer,Renzong Qiu,Alastair Kent,Kazuto Kato,Norio Niikawa,Isaac F. Adewole,Bartha Maria Knoppers,Morris W. Foster,Ellen Wright Clayton,Jessica Watkin,Richard A. Gibbs,Donna M. Muzny,Lynne V. Nazareth,Erica Sodergren,George M. Weinstock,Imtiaz Yakub,Stacey Gabriel,Robert C. Onofrio,Liuda Ziaugra,Bruce W. Birren,Mark J. Daly,Richard K. Wilson,Lucinda Fulton,Jane Rogers,John Burton,Nigel P. Carter,C M Clee,Mark Griffiths,Matthew C. Jones,Kirsten McLay,Robert W. Plumb,Mark T. Ross,Sarah Sims,David Willey,Zhu Chen,Hua Han,L. Kang,Martin Godbout,John C. Wallenburg,Paul L'Archevêque,Guy Bellemare,Koji Saeki,Hongguang Wang,Daochang An,Hongbo Fu,Qing Li,Zhen Wang,Renwu Wang,Arthur L. Holden,Lisa D. Brooks,Jean E. McEwen,Christianne R. Bird,Mark S. Guyer,Patrick J. Nailer,Vivian Ota Wang,Jane Peterson,Michael Shi,Jack Spiegel,Lawrence M. Sung,Jonathan Witonsky,Lynn F. Zacharia,Francis S. Collins,Karen Kennedy,Ruth Jamieson,John Stewart +232 more
TL;DR: A public database of common variation in the human genome: more than one million single nucleotide polymorphisms for which accurate and complete genotypes have been obtained in 269 DNA samples from four populations, including ten 500-kilobase regions in which essentially all information about common DNA variation has been extracted.
Journal ArticleDOI
A flexible and accurate genotype imputation method for the next generation of genome-wide association studies.
TL;DR: It is found that imputation accuracy can be greatly enhanced by expanding the reference panel to contain thousands of chromosomes and that IMPUTE v2 outperforms other methods in this setting at both rare and common SNPs, with overall error rates that are 15%–20% lower than those of the closest competing method.
Journal ArticleDOI
A Comparison of Bayesian Methods for Haplotype Reconstruction from Population Genotype Data
Matthew Stephens,Peter Donnelly +1 more
TL;DR: A new algorithm is introduced that combines the modeling strategy of one method with the computational strategies of another and outperforms all three existing methods for inferring haplotypes from genotype data in a population sample.
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