Estimation of effect size distribution from genome-wide association studies and implications for future discoveries

被引：518

作者：

Park, Ju-Hyun ^{[1
]}

Wacholder, Sholom ^{[1
]}

Gail, Mitchell H. ^{[1
]}

Peters, Ulrike ^{[2
]}

Jacobs, Kevin B. ^{[3
]}

Chanock, Stephen J. ^{[1
,3
]}

Chatterjee, Nilanjan ^{[1
]}

机构：

[1] NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Rockville, MD USA

[2] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA

[3] NCI, Core Genotyping Facil, NIH, US Dept HHS, Gaithersburg, MD USA

来源：

NATURE GENETICS | 2010年 / 42卷 / 07期

基金：

美国国家卫生研究院;

关键词：

BREAST-CANCER; SUSCEPTIBILITY LOCI; GENETIC ASSOCIATION; RISK ALLELES; ODDS RATIOS; VARIANTS; POWER; IDENTIFICATION;

D O I：

10.1038/ng.610

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

We report a set of tools to estimate the number of susceptibility loci and the distribution of their effect sizes for a trait on the basis of discoveries from existing genome-wide association studies (GWASs). We propose statistical power calculations for future GWASs using estimated distributions of effect sizes. Using reported GWAS findings for height, Crohn's disease and breast, prostate and colorectal (BPC) cancers, we determine that each of these traits is likely to harbor additional loci within the spectrum of low-penetrance common variants. These loci, which can be identified from sufficiently powerful GWASs, together could explain at least 15-20% of the known heritability of these traits. However, for BPC cancers, which have modest familial aggregation, our analysis suggests that risk models based on common variants alone will have modest discriminatory power (63.5% area under curve), even with new discoveries.

引用

页码：570 / U139

页数：8

共 36 条

[1] Power for genetic association studies with random allele frequencies and genotype distributions [J].

Ambrosius, WT ;

Lange, EM ;

Langefeld, CD .

AMERICAN JOURNAL OF HUMAN GENETICS, 2004, 74 (04) :683-693

[2] Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease [J].

Barrett, Jeffrey C. ;

Hansoul, Sarah ;

Nicolae, Dan L. ;

Cho, Judy H. ;

Duerr, Richard H. ;

Rioux, John D. ;

Brant, Steven R. ;

Silverberg, Mark S. ;

Taylor, Kent D. ;

Barmada, M. Michael ;

Bitton, Alain ;

Dassopoulos, Themistocles ;

Datta, Lisa Wu ;

Green, Todd ;

Griffiths, Anne M. ;

Kistner, Emily O. ;

Murtha, Michael T. ;

Regueiro, Miguel D. ;

Rotter, Jerome I. ;

Schumm, L. Philip ;

Steinhart, A. Hillary ;

Targan, Stephan R. ;

Xavier, Ramnik J. ;

Libioulle, Cecile ;

Sandor, Cynthia ;

Lathrop, Mark ;

Belaiche, Jacques ;

Dewit, Olivier ;

Gut, Ivo ;

Heath, Simon ;

Laukens, Debby ;

Mni, Myriam ;

Rutgeerts, Paul ;

Van Gossum, Andre ;

Zelenika, Diana ;

Franchimont, Denis ;

Hugot, Jean-Pierre ;

de Vos, Martine ;

Vermeire, Severine ;

Louis, Edouard ;

Cardon, Lon R. ;

Anderson, Carl A. ;

Drummond, Hazel ;

Nimmo, Elaine ;

Ahmad, Tariq ;

Prescott, Natalie J. ;

Onnie, Clive M. ;

Fisher, Sheila A. ;

Marchini, Jonathan ;

Ghori, Jilur .

NATURE GENETICS, 2008, 40 (08) :955-962

[3] Rare Variants Create Synthetic Genome-Wide Associations [J].

Dickson, Samuel P. ;

Wang, Kai ;

Krantz, Ian ;

Hakonarson, Hakon ;

Goldstein, David B. .

PLOS BIOLOGY, 2010, 8 (01)

[4] Genome-wide association study identifies novel breast cancer susceptibility loci [J].

Easton, Douglas F. ;

Pooley, Karen A. ;

Dunning, Alison M. ;

Pharoah, Paul D. P. ;

Thompson, Deborah ;

Ballinger, Dennis G. ;

Struewing, Jeffery P. ;

Morrison, Jonathan ;

Field, Helen ;

Luben, Robert ;

Wareham, Nicholas ;

Ahmed, Shahana ;

Healey, Catherine S. ;

Bowman, Richard ;

Meyer, Kerstin B. ;

Haiman, Christopher A. ;

Kolonel, Laurence K. ;

Henderson, Brian E. ;

Le Marchand, Loic ;

Brennan, Paul ;

Sangrajrang, Suleeporn ;

Gaborieau, Valerie ;

Odefrey, Fabrice ;

Shen, Chen-Yang ;

Wu, Pei-Ei ;

Wang, Hui-Chun ;

Eccles, Diana ;

Evans, D. Gareth ;

Peto, Julian ;

Fletcher, Olivia ;

Johnson, Nichola ;

Seal, Sheila ;

Stratton, Michael R. ;

Rahman, Nazneen ;

Chenevix-Trench, Georgia ;

Bojesen, Stig E. ;

Nordestgaard, Borge G. ;

Axelsson, Christen K. ;

Garcia-Closas, Montserrat ;

Brinton, Louise ;

Chanock, Stephen ;

Lissowska, Jolanta ;

Peplonska, Beata ;

Nevanlinna, Heli ;

Fagerholm, Rainer ;

Eerola, Hannaleena ;

Kang, Daehee ;

Yoo, Keun-Young ;

Noh, Dong-Young ;

Ahn, Sei-Hyun .

NATURE, 2007, 447 (7148) :1087-U7

[5] Power to detect risk Alleles using genome-wide tag SNP panels [J].

Eberle, Michael A. ;

Ng, Pauline C. ;

Kuhn, Kenneth ;

Zhou, Lixin ;

Peiffer, Daniel A. ;

Galver, Luana ;

Viaud-Martinez, Karine A. ;

Lawley, Cynthia Taylor ;

Gunderson, Kevin L. ;

Shen, Richard ;

Murray, Sarah S. .

PLOS GENETICS, 2007, 3 (10) :1827-1837

[6] Multiple newly identified loci associated with prostate cancer susceptibility [J].

Eeles, Rosalind A. ;

Kote-Jarai, Zsofia ;

Giles, Graham G. ;

Al Olama, Ali Amin ;

Guy, Michelle ;

Jugurnauth, Sarah K. ;

Mulholland, Shani ;

Leongamornlert, Daniel A. ;

Edwards, Stephen M. ;

Morrison, Jonathan ;

Field, Helen I. ;

Southey, Melissa C. ;

Severi, Gianluca ;

Donovan, Jenny L. ;

Hamdy, Freddie C. ;

Dearnaley, David P. ;

Muir, Kenneth R. ;

Smith, Charmaine ;

Bagnato, Melisa ;

Ardern-Jones, Audrey T. ;

Hall, Amanda L. ;

O'Brien, Lynne T. ;

Gehr-Swain, Beatrice N. ;

Wilkinson, Rosemary A. ;

Cox, Angie ;

Lewis, Sarah ;

Brown, Paul M. ;

Jhavar, Sameer G. ;

Tymrakiewicz, Malgorzata ;

Lophatananon, Artitaya ;

Bryant, Sarah L. ;

Horwich, Alan ;

Huddart, Robert A. ;

Khoo, Vincent S. ;

Parker, Christopher C. ;

Woodhouse, Christopher J. ;

Thompson, Alan ;

Christmas, Tim ;

Ogden, Chris ;

Fisher, Cyril ;

Jamieson, Charles ;

Cooper, Colin S. ;

English, Dallas R. ;

Hopper, John L. ;

Neal, David E. ;

Easton, Douglas F. .

NATURE GENETICS, 2008, 40 (03) :316-321

[7] Identification of seven new prostate cancer susceptibility loci through a genome-wide association study [J].

Eeles, Rosalind A. ;

Kote-Jarai, Zsofia ;

Al Olama, Ali Amin ;

Giles, Graham G. ;

Guy, Michelle ;

Severi, Gianluca ;

Muir, Kenneth ;

Hopper, John L. ;

Henderson, Brian E. ;

Haiman, Christopher A. ;

Schleutker, Johanna ;

Hamdy, Freddie C. ;

Neal, David E. ;

Donovan, Jenny L. ;

Stanford, Janet L. ;

Ostrander, Elaine A. ;

Ingles, Sue A. ;

John, Esther M. ;

Thibodeau, Stephen N. ;

Schaid, Daniel ;

Park, Jong Y. ;

Spurdle, Amanda ;

Clements, Judith ;

Dickinson, Joanne L. ;

Maier, Christiane ;

Vogel, Walther ;

Doerk, Thilo ;

Rebbeck, Timothy R. ;

Cooney, Kathleen A. ;

Cannon-Albright, Lisa ;

Chappuis, Pierre O. ;

Hutter, Pierre ;

Zeegers, Maurice ;

Kaneva, Radka ;

Zhang, Hong-Wei ;

Lu, Yong-Jie ;

Foulkes, William D. ;

English, Dallas R. ;

Leongamornlert, Daniel A. ;

Tymrakiewicz, Malgorzata ;

Morrison, Jonathan ;

Ardern-Jones, Audrey T. ;

Hall, Amanda L. ;

O'Brien, Lynne T. ;

Wilkinson, Rosemary A. ;

Saunders, Edward J. ;

Page, Elizabeth C. ;

Sawyer, Emma J. ;

Edwards, Stephen M. ;

Dearnaley, David P. .

NATURE GENETICS, 2009, 41 (10) :1116-U97

[8] Discriminatory accuracy from single-nucleotide polymorphisms in models to predict breast cancer risk [J].

Gail, Mitchell H. .

JOURNAL OF THE NATIONAL CANCER INSTITUTE, 2008, 100 (14) :1037-1041

[9] Value of Adding Single-Nucleotide Polymorphism Genotypes to a Breast Cancer Risk Model [J].

Gail, Mitchell H. .

JOURNAL OF THE NATIONAL CANCER INSTITUTE, 2009, 101 (13) :959-963

[10] Estimating odds ratios in genome scans: An approximate conditional likelihood approach [J].

Ghosh, Arpita ;

Zou, Fei ;

Wright, Fred A. .

AMERICAN JOURNAL OF HUMAN GENETICS, 2008, 82 (05) :1064-1074

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