Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease
Gosia Trynka,Karen A. Hunt,Nicholas A. Bockett,Jihane Romanos,Vanisha Mistry,Agata Szperl,Sjoerd F. Bakker,Maria Teresa Bardella,Leena Bhaw-Rosun,Gemma Castillejo,Emilio G. de la Concha,Rodrigo Coutinho de Almeida,Kerith-Rae Dias,Cleo C. van Diemen,Patrick Dubois,Richard H. Duerr,Sarah Edkins,Lude Franke,Karin Fransen,Javier Gutierrez,Graham A. Heap,Barbara Hrdličková,Sarah E. Hunt,Leticia Plaza Izurieta,V. Izzo,Leo A. B. Joosten,Cordelia Langford,Maria Cristina Mazzilli,Charles A. Mein,Vandana Midah,Mitja Mitrovic,Barbara Mora,Marinita Morelli,Sarah Nutland,Concepción Núñez,Suna Onengut-Gumuscu,Kerra Pearce,Mathieu Platteel,Isabel Polanco,Simon C. Potter,Carmen Ribes-Koninckx,Isis Ricaño-Ponce,Stephen S. Rich,Anna Rybak,Jose Luis Santiago,Sabyasachi Senapati,Ajit Sood,Hania Szajewska,Riccardo Troncone,Jezabel Varadé,Chris Wallace,Victorien M. Wolters,Alexandra Zhernakova,B.K. Thelma,Bożena Cukrowska,Elena Urcelay,Jose Ramon Bilbao,M. Luisa Mearin,Donatella Barisani,Jeffrey C. Barrett,Vincent Plagnol,Panos Deloukas,Cisca Wijmenga,David A. van Heel +63 more
TLDR
The complex genetic architecture of the risk regions of and refine the risk signals for celiac disease are defined, providing the next step toward uncovering the causal mechanisms of the disease.Abstract:
Using variants from the 1000 Genomes Project pilot European CEU dataset and data from additional resequencing studies, we densely genotyped 183 non-HLA risk loci previously associated with immune-mediated diseases in 12,041 individuals with celiac disease (cases) and 12,228 controls. We identified 13 new celiac disease risk loci reaching genome-wide significance, bringing the number of known loci (including the HLA locus) to 40. We found multiple independent association signals at over one-third of these loci, a finding that is attributable to a combination of common, low-frequency and rare genetic variants. Compared to previously available data such as those from HapMap3, our dense genotyping in a large sample collection provided a higher resolution of the pattern of linkage disequilibrium and suggested localization of many signals to finer scale regions. In particular, 29 of the 54 fine-mapped signals seemed to be localized to single genes and, in some instances, to gene regulatory elements. Altogether, we define the complex genetic architecture of the risk regions of and refine the risk signals for celiac disease, providing the next step toward uncovering the causal mechanisms of the disease.read more
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A global reference for human genetic variation.
Adam Auton,Gonçalo R. Abecasis,David Altshuler,Richard Durbin,David R. Bentley,Aravinda Chakravarti,Andrew G. Clark,Peter Donnelly,Evan E. Eichler,Paul Flicek,Stacey Gabriel,Richard A. Gibbs,Eric D. Green,Matthew E. Hurles,Bartha Maria Knoppers,Jan O. Korbel,Eric S. Lander,Charles Lee,Hans Lehrach,Elaine R. Mardis,Gabor T. Marth,Gil McVean,Deborah A. Nickerson,Jeanette Schmidt,Stephen T. Sherry,Jun Wang,Richard K. Wilson,Eric Boerwinkle,Harsha Doddapaneni,Yi Han,Viktoriya Korchina,Christie Kovar,Sandra L. Lee,Donna M. Muzny,Jeffrey G. Reid,Yiming Zhu,Yuqi Chang,Qiang Feng,Qiang Feng,Xiaodong Fang,Xiaodong Fang,Xiaosen Guo,Xiaosen Guo,Min Jian,Min Jian,Hui Jiang,Hui Jiang,Xin Jin,Tianming Lan,Guoqing Li,Jingxiang Li,Yingrui Li,Shengmao Liu,Xiao Liu,Xiao Liu,Yao Lu,Xuedi Ma,Meifang Tang,Bo Wang,Guangbiao Wang,Honglong Wu,Renhua Wu,Xun Xu,Ye Yin,Dandan Zhang,Wenwei Zhang,Jiao Zhao,Meiru Zhao,Xiaole Zheng,Namrata Gupta,Neda Gharani,Lorraine Toji,Norman P. Gerry,Alissa M. Resch,Jonathan Barker,Laura Clarke,Laurent Gil,Sarah E. Hunt,Gavin Kelman,Eugene Kulesha,Rasko Leinonen,William M. McLaren,Rajesh Radhakrishnan,Asier Roa,Dmitriy Smirnov,Richard Smith,Ian Streeter,Anja Thormann,Iliana Toneva,Brendan Vaughan,Xiangqun Zheng-Bradley,Russell J. Grocock,Sean Humphray,Terena James,Zoya Kingsbury,Ralf Sudbrak,M. Albrecht,Vyacheslav Amstislavskiy,Tatiana A. Borodina,Matthias Lienhard,Florian Mertes,Marc Sultan,Bernd Timmermann,Marie-Laure Yaspo,Lucinda Fulton,Victor Ananiev,Zinaida Belaia,Dimitriy Beloslyudtsev,Nathan Bouk,Chao Chen,Deanna M. Church,Robert M. Cohen,Charles Cook,John Garner,Timothy Hefferon,Mikhail Kimelman,Chunlei Liu,John Lopez,Peter Meric,Chris O’Sullivan,Yuri Ostapchuk,Lon Phan,Sergiy Ponomarov,Valerie A. Schneider,Eugene Shekhtman,Karl Sirotkin,Douglas J. Slotta,Hua Zhang,Senduran Balasubramaniam,John Burton,Petr Danecek,Thomas M. Keane,Anja Kolb-Kokocinski,Shane A. McCarthy,James Stalker,Michael A. 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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
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
The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019.
Annalisa Buniello,Jacqueline A. L. MacArthur,Maria Cerezo,Laura W. Harris,James D. Hayhurst,Cinzia Malangone,Aoife McMahon,Joannella Morales,Edward Mountjoy,Edward Mountjoy,Elliot Sollis,Daniel Suveges,Olga Vrousgou,Patricia L. Whetzel,M. Ridwan Amode,Jose A. Guillen,Harpreet Singh Riat,Stephen J. Trevanion,Peggy Hall,Heather Junkins,Paul Flicek,Tony Burdett,Lucia A. Hindorff,Fiona Cunningham,Helen Parkinson +24 more
TL;DR: Improved data access is improved with the release of a new RESTful API to support high-throughput programmatic access, an improved web interface and a new summary statistics database.
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
Bayesian test for colocalisation between pairs of genetic association studies using summary statistics.
Claudia Giambartolomei,Damjan Vukcevic,Eric E. Schadt,Lude Franke,Aroon D. Hingorani,Chris Wallace,Vincent Plagnol +6 more
TL;DR: A novel statistical methodology to assess whether two association signals are consistent with a shared causal variant and the ability to derive the output statistics from single SNP summary statistics, making it possible to perform systematic meta-analysis type comparisons across multiple GWAS datasets is developed.
Journal ArticleDOI
Genetic and Epigenetic Fine-Mapping of Causal Autoimmune Disease Variants
Kyle Kai-How Farh,Alexander Marson,Jiang Zhu,Markus Kleinewietfeld,William J. Housley,Samantha Beik,Noam Shoresh,Holly Whitton,Russell J.H. Ryan,Alexander A. Shishkin,Meital Hatan,Marlene J. Carrasco-Alfonso,Dita Mayer,C. John Luckey,Nikolaos A. Patsopoulos,Philip L. De Jager,Vijay K. Kuchroo,Charles B. Epstein,Mark J. Daly,David A. Hafler,Bradley E. Bernstein +20 more
TL;DR: A fine-mapping algorithm is developed to identify candidate causal variants for 21 autoimmune diseases from genotyping data, and it is found that most non-coding risk variants, including those that alter gene expression, affect non-canonical sequence determinants not well-explained by current gene regulatory models.
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Journal ArticleDOI
A Map of Human Genome Variation From Population-Scale Sequencing
Gonçalo R. Abecasis,David Altshuler,David Altshuler,Adam Auton,Lisa D Brooks,Richard Durbin,Richard A. Gibbs,Matthew E. Hurles,Gil McVean +8 more
TL;DR: The 1000 Genomes Project aims to provide a deep characterization of human genome sequence variation as a foundation for investigating the relationship between genotype and phenotype as mentioned in this paper, and the results of the pilot phase of the project, designed to develop and compare different strategies for genomewide sequencing with high-throughput platforms.
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Table S2: Trans-factors and trinucleotide repeat instability Trans-factor
Journal ArticleDOI
LocusZoom: regional visualization of genome-wide association scan results
Randall Pruim,Ryan P. Welch,Serena Sanna,Tanya M. Teslovich,Peter S. Chines,Terry P. Gliedt,Michael Boehnke,Gonçalo R. Abecasis,Cristen J. Willer +8 more
TL;DR: LocusZoom is a web-based plotting tool that provides fast visual display of GWAS results in a publication-ready format that visually displays regional information such as the strength and extent of the association signal relative to genomic position, local linkage disequilibrium (LD) and recombination patterns and the positions of genes in the region.
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