Open Access
Discovery of common and rare genetic risk variants for colorectal cancer
Jeroen R. Huyghe,Stephanie A. Bien,Tabitha A. Harrison,Hyun Min Kang,Sai Chen,Stephanie L. Schmit,David V. Conti,Conghui Qu,Jihyoun Jeon,Christopher K. Edlund,Peyton Greenside,Michael Wainberg,Fredrick R. Schumacher,Joshua D. Smith,David M. Levine,Sarah C. Nelson,Nasa Sinnott-Armstrong,Demetrius Albanes,M. Henar Alonso,Kristin E. Anderson,Coral Arnau-Collell,Volker Arndt,Christina Bamia,Barbara L. Banbury,John A. Baron,Sonja I. Berndt,Stéphane Bézieau,D. Timothy Bishop,Juergen Boehm,Heiner Boeing,Hermann Brenner,Stefanie Brezina,Stephan Buch,Daniel D. Buchanan,Andrea N. Burnett-Hartman,Katja Butterbach,Bette J. Caan,Peter T. Campbell,Christopher S. Carlson,Sergi Castellví-Bel,Andrew T. Chan,Jenny Chang-Claude,Stephen J. Chanock,María Dolores Chirlaque,Sang-Hee Cho,Charles M. Connolly,Amanda J. Cross,Katarina Cuk,Keith R. Curtis,Albert de la Chapelle,Kimberly F. Doheny,David Duggan,Douglas F. Easton,Sjoerd G. Elias,Faye Elliott,Dallas R. English,Edith J. M. Feskens,Jane C. Figueiredo,Rocky Fischer,Liesel M. FitzGerald,David Forman,Manish Gala,Steven Gallinger,W. James Gauderman,Graham G. Giles,Elizabeth M. Gillanders,Jian Gong,Phyllis J. Goodman,William M. Grady,John S. Grove,Andrea Gsur,Marc J. Gunter,Robert W. Haile,Jochen Hampe,Heather Hampel,Sophia Harlid,Richard B. Hayes,Philipp Hofer,Michael Hoffmeister,John L. Hopper,Wan-Ling Hsu,Wen-Yi Huang,Thomas J. Hudson,David J. Hunter,Gemma Ibáñez-Sanz,Gregory Idos,Roxann G. Ingersoll,Rebecca D. Jackson,Eric J. Jacobs,Mark A. Jenkins,Amit Joshi,Corinne E. Joshu,Temitope O. Keku,Timothy J. Key,Hyeong Rok Kim,Emiko Kobayashi,Laurence N. Kolonel,Charles Kooperberg,Tilman Kuehn,Sébastien Küry,Sun-Seog Kweon,Susanna C. Larsson,Cecelia A. Laurie,Loic Le Marchand,Suzanne M. Leal,Soo-Chin Lee,Flavio Lejbkowicz,Mathieu Lemire,Christopher I. Li,Li Li,Wolfgang Lieb,Yi Lin,Annika Lindblom,Noralane M. Lindor,Hua Ling,Tin Louie,Satu Männistö,Sanford D. Markowitz,Vicente Martín,Giovanna Masala,Caroline McNeil,Marilena Melas,Roger L. Milne,Lorena Moreno,Neil Murphy,Robin Myte,Alessio Naccarati,Polly A. Newcomb,Kenneth Offit,Shuji Ogino,N. Charlotte Onland-Moret,Barbara Pardini,Patrick S. Parfrey,Rachel Pearlman,Vittorio Perduca,Paul D.P. Pharoah,Mila Pinchev,Elizabeth A. Platz,Ross L. Prentice,Elizabeth W. Pugh,Leon Raskin,Gad Rennert,Hedy S. Rennert,Elio Riboli,Miguel Rodríguez-Barranco,Jane Romm,Lori C. Sakoda,Clemens Schafmayer,Robert E. Schoen,Daniela Seminara,Mitul Shah,Tameka Shelford,Min-Ho Shin,Katerina Shulman,Sabina Sieri,Martha L. Slattery,Melissa C. Southey,Zsofia K. Stadler,Christa Stegmaier,Yu-Ru Su,Catherine M. Tangen,Stephen N. Thibodeau,Duncan C. Thomas,Sushma S. Thomas,Amanda E. Toland,Antonia Trichopoulou,Cornelia M. Ulrich,David Van Den Berg,Fränzel J.B. Van Duijnhoven,Bethany Van Guelpen,Henk J. van Kranen,Joseph Vijai,Kala Visvanathan,Pavel Vodicka,Ludmila Vodickova,Veronika Vymetalkova,Korbinian Weigl,Stephanie J. Weinstein,Emily White,Aung Ko Win,C. Roland Wolf,Alicja Wolk,Michael O. Woods,Anna H. Wu,Syed H.E. Zaidi,Brent W. Zanke,Qing Zhang,Wei Zheng,Peter C. Scacheri,John D. Potter,Michael C. Bassik,Anshul Kundaje,Graham Casey,Victor Moreno,Gonçalo R. Abecasis,Deborah A. Nickerson,Stephen B. Gruber,Li Hsu,Ulrike Peters +198 more
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TLDR
The authors in this article performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls.Abstract:
To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10−8, bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.Genome-wide association analyses based on whole-genome sequencing and imputation identify 40 new risk variants for colorectal cancer, including a strongly protective low-frequency variant at CHD1 and loci implicating signaling and immune function in disease etiology.read more
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Integrative analysis of 111 reference human epigenomes
Anshul Kundaje,Wouter Meuleman,Jason Ernst,Angela Yen,Pouya Kheradpour,Zhizhuo Zhang,Jianrong Wang,Lucas D. Ward,Abhishek Sarkar,Gerald Quon,Matthew L. Eaton,Yi-Chieh Wu,Andreas R. Pfenning,Xinchen Wang,Melina Claussnitzer,Yaping Liu,Mukul S. Bansal,Soheil Feizi-Khankandi,Ah Ram Kim,Richard C Sallari,Nicholas A Sinnott-Armstrong,Laurie A. Boyer,Elizabeta Gjoneska,Li-Huei Tsai,Manolis Kellis +24 more
TL;DR: In this article, the authors describe the integrative analysis of 111 reference human epigenomes generated as part of the NIH Roadmap Epigenomics Consortium, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression.
The genetic architecture of type 2 diabetes
Christian Fuchsberger,Jason Flannick,Tanya M. Teslovich,Anubha Mahajan,Vineeta Agarwala,Kyle J. Gaulton,Clement Ma,Pierre Fontanillas,Loukas Moutsianas,Davis J. McCarthy,Manuel A. Rivas,John R. B. Perry,Xueling Sim,Thomas W. Blackwell,Neil Robertson,N. William Rayner,Pablo Cingolani,Adam E. Locke,Juan Fernandez Tajes,Heather M. Highland,Josée Dupuis,Peter S. Chines,Cecilia M. Lindgren,Christopher Hartl,Anne U. Jackson,Han Chen,Jeroen R. Huyghe,Martijn van de Bunt,Richard D. Pearson,Ashok Kumar,Martina Mueller-Nurasyid,Niels Grarup,Heather M. Stringham,Eric R. Gamazon,Jae-Hoon Lee,Yi Chen,Robert A. Scott,Jennifer E. Below,Peng Chen,Jinyan Huang,Min Jin Go,Michael L. Stitzel,Dorota Pasko,Stephen C. J. Parker,Tibor V. Varga,Todd Green,Nicola L. Beer,Aaron G. Day-Williams,Teresa Ferreira,Tasha E. Fingerlin,Momoko Horikoshi,Cheng Hu,Iksoo Huh,Mohammad Kamran Ikram,Bong-Jo Kim,Yongkang Kim,Young-Jin Kim,Min-Seok Kwon,Juyoung Lee,Selyeong Lee,Keng-Han Lin,Taylor J. Maxwell,Yoshihiko Nagai,Xu Wang,Ryan P. Welch,Joon Yoon,Weihua Zhang,Nir Barzilai,Benjamin F. Voight,Bok-Ghee Han,Christopher P. Jenkinson,Teemu Kuulasmaa,Johanna Kuusisto,Alisa K. Manning,Maggie C.Y. Ng,Nicholette D. Palmer,Beverley Balkau,Alena Stančáková,Hanna E. Abboud,Heiner Boeing,Vilmantas Giedraitis,Dorairaj Prabhakaran,Omri Gottesman,James Scott,Jason Carey,Phoenix Kwan,George B. Grant,Joshua D. Smith,Benjamin M. Neale,Shaun Purcell,Adam S. Butterworth,Joanna M. M. Howson,Heung Man Lee,Yingchang Lu,Soo Heon Kwak,Wei Zhao,John Danesh,Vincent K. L. Lam,Kyong Soo Park,Danish Saleheen,Wing-Yee So,Claudia H. T. Tam,Uzma Afzal,David Aguilar,Rector Arya,Tin Aung,Edmund Chan,Carmen Navarro,Ching-Yu Cheng,Domenico Palli,Adolfo Correa,Joanne E. Curran,Denis Rybin,Vidya S. Farook,Sharon P. Fowler,Barry I. Freedman,Michael Griswold,Daniel E. Hale,Pamela J. Hicks,Chiea Chuen Khor,Satish Kumar,Benjamin Lehne,Dorothée Thuillier,Wei-Yen Lim,Jianjun Liu,Yvonne T. van der Schouw,Marie Loh,Solomon K. Musani,Sobha Puppala,William R. Scott,Loic Yengo,Sian-Tsung Tan,Herman A. Taylor,Farook Thameem,Gregory P. Wilson,Tien Yin Wong,Pål R. Njølstad,Jonathan C. Levy,Massimo Mangino,Lori L. Bonnycastle,Thomas Schwarzmayr,João Fadista,Gabriela L. Surdulescu,Christian Herder,Christopher J. Groves,Thomas Wieland,Jette Bork-Jensen,Ivan Brandslund,Cramer Christensen,Heikki A. Koistinen,Alex S. F. Doney,Leena Kinnunen,Tõnu Esko,Andrew Farmer,Liisa Hakaste,Dylan Hodgkiss,Jasmina Kravic,Valeriya Lyssenko,Mette Hollensted,Marit E. Jørgensen,Torben Jørgensen,Claes Ladenvall,Johanne Marie Justesen,Annemari Käräjämäki,Jennifer Kriebel,Wolfgang Rathmann,Lars Lannfelt,Torsten Lauritzen,Narisu Narisu,Allan Linneberg,Olle Melander,Lili Milani,Matt Neville,Marju Orho-Melander,Lu Qi,Qibin Qi,Michael Roden,Olov Rolandsson,Amy J. Swift,Anders Rosengren,Kathleen Stirrups,Andrew R. Wood,Evelin Mihailov,Christine Blancher,Mauricio O. Carneiro,Jared Maguire,Ryan Poplin,Khalid Shakir,Timothy R. Fennell,Mark A. DePristo,Martin Hrabé de Angelis,Panos Deloukas,Anette P. Gjesing,Goo Jun,Peter M. Nilsson,Jacquelyn Murphy,Robert C. Onofrio,Barbara Thorand,Torben Hansen,Christa Meisinger,Frank B. Hu,Bo Isomaa,Fredrik Karpe,Liming Liang,Annette Peters,Cornelia Huth,Stephen O'Rahilly,Colin N. A. Palmer,Oluf Pedersen,Rainer Rauramaa,Jaakko Tuomilehto,Veikko Salomaa,Richard M. Watanabe,Ann-Christine Syvänen,Richard N. Bergman,Dwaipayan Bharadwaj,Erwin P. Bottinger,Yoon Shin Cho,Giriraj R. Chandak,Juliana C.N. Chan,Kee Seng Chia,Mark J. Daly,Shah Ebrahim,Claudia Langenberg,Paul Elliott,Kathleen A. Jablonski,Donna M. Lehman,Weiping Jia,Ronald C.W. Ma,Toni I. Pollin,Manjinder S. Sandhu,Nikhil Tandon,Philippe Froguel,Inês Barroso,Yik Ying Teo,Eleftheria Zeggini,Ruth J. F. Loos,Kerrin S. Small,Janina S. Ried,Ralph A. DeFronzo,Harald Grallert,Benjamin Glaser,Andres Metspalu,Nicholas J. Wareham,Mark Walker,Eric Banks,Christian Gieger,Erik Ingelsson,Hae Kyung Im,Thomas Illig,Paul W. Franks,Gemma Buck,Joseph Trakalo,David Buck,Inga Prokopenko,Reedik Mägi,Lars Lind,Yossi Farjoun,Katharine R. Owen,Anna L. Gloyn,Konstantin Strauch,Tiinamaija Tuomi,Jaspal S. Kooner,Jong-Young Lee,Taesung Park,Peter Donnelly,Andrew D. Morris,Andrew T. Hattersley,Donald W. Bowden,Francis S. Collins,Gil Atzmon,John C. Chambers,Tim D. Spector,Markku Laakso,Tim M. Strom,Graeme I. Bell,John Blangero,Ravindranath Duggirala,E. Shyong Tai,Gilean McVean,Craig L. Hanis,James G. Wilson,Mark Seielstad,Timothy M. Frayling,James B. Meigs,Nancy J. Cox,Robert Sladek,Eric S. Lander,Stacey Gabriel,Noël P. Burtt,Karen L. Mohlke,Thomas Meitinger,Leif Groop,Gonçalo R. Abecasis,Jose C. Florez,Laura J. Scott,Andrew P. Morris,Hyun Min Kang,Michael Boehnke,David Altshuler,Mark I. McCarthy +300 more
TL;DR: Large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes, but most fell within regions previously identified by genome-wide association studies.
Genomic inflation factors under polygenic inheritance
Jian Yang,Michael N. Weedon,Shaun Purcell,Shaun Purcell,Guillaume Lettre,Karol Estrada,Cristen J. Willer,Albert V. Smith,Erik Ingelsson,Jeffrey R. O'Connell,Massimo Mangino,Reedik Mägi,Pamela A. F. Madden,Andrew C. Heath,Dale R. Nyholt,Nicholas G. Martin,Grant W. Montgomery,Timothy M. Frayling,Joel N. Hirschhorn,Joel N. Hirschhorn,Joel N. Hirschhorn,Mark I. McCarthy,Mark I. McCarthy,Michael E. Goddard,Peter M. Visscher +24 more
TL;DR: In this paper, the authors show that in the absence of population structure and other technical artefacts, but in the presence of polygenic inheritance, substantial genomic inflation is expected, its magnitude depends on sample size, heritability, linkage disequilibrium structure and the number of causal variants.
Journal Article
RGMb is a novel binding partner for PD-L2 and its engagement with PD-L2 promotes respiratory tolerance (IRC5P.465)
Yanping Xiao,Sanhong Yu,Baogong Zhu,Denis Bedoret,Xia Bu,Loise M. Francisco,Ping Hua,Jonathan S. Duke-Cohan,Dale T. Umetsu,Arlene H. Sharpe,Arlene H. Sharpe,Rosemarie H. DeKruyff,Gordon J. Freeman +12 more
TL;DR: In this article, the authors showed that PD-L2 binding to repulsive guidance molecule b (RGMb) significantly impaired the development of respiratory tolerance by interfering with the initial T cell expansion required for respiratory tolerance.
References
More filters
Journal ArticleDOI
Fast and accurate short read alignment with Burrows–Wheeler transform
Heng Li,Richard Durbin +1 more
TL;DR: Burrows-Wheeler Alignment tool (BWA) is implemented, a new read alignment package that is based on backward search with Burrows–Wheeler Transform (BWT), to efficiently align short sequencing reads against a large reference sequence such as the human genome, allowing mismatches and gaps.
Journal ArticleDOI
Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.
Suzanne L. Topalian,F. Stephen Hodi,Julie R. Brahmer,Scott N. Gettinger,David Smith,David F. McDermott,John D. Powderly,Richard D. Carvajal,Jeffrey A. Sosman,Michael B. Atkins,Philip D. Leming,David R. Spigel,Scott J. Antonia,Leora Horn,Charles G. Drake,Drew M. Pardoll,Lieping Chen,William H. Sharfman,Robert A. Anders,Janis M. Taube,Tracee L. McMiller,Haiying Xu,Alan J. Korman,Maria Jure-Kunkel,Shruti Agrawal,Dan McDonald,Georgia Kollia,Ashok Kumar Gupta,Jon M. Wigginton,Mario Sznol +29 more
TL;DR: Anti-PD-1 antibody produced objective responses in approximately one in four to one in five patients with non-small-cell lung cancer, melanoma, or renal-cell cancer; the adverse-event profile does not appear to preclude its use.
Journal ArticleDOI
ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data
TL;DR: The ANNOVAR tool to annotate single nucleotide variants and insertions/deletions, such as examining their functional consequence on genes, inferring cytogenetic bands, reporting functional importance scores, finding variants in conserved regions, or identifying variants reported in the 1000 Genomes Project and dbSNP is developed.
Journal ArticleDOI
An integrated map of genetic variation from 1,092 human genomes
Gonçalo R. Abecasis,Adam Auton,Lisa D. Brooks,Mark A. DePristo,Richard Durbin,Robert E. Handsaker,Robert E. Handsaker,Hyun Min Kang,Gabor T. Marth,Gil McVean +9 more
TL;DR: It is shown that evolutionary conservation and coding consequence are key determinants of the strength of purifying selection, that rare-variant load varies substantially across biological pathways, and that each individual contains hundreds of rare non-coding variants at conserved sites, such as motif-disrupting changes in transcription-factor-binding sites.
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.