PRIMe: a method for characterization and evaluation of pleiotropic regions from multiple genome-wide association studies

被引:51
作者
Huang, Jie [1 ,2 ]
Johnson, Andrew D. [1 ,2 ]
O'Donnell, Christopher J. [1 ,2 ,3 ]
机构
[1] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA
[2] NHLBI, Div Intramural Res, Bethesda, MD 20824 USA
[3] Harvard Univ, Div Cardiol, Sch Med, Dept Med,Massachusetts Gen Hosp, Boston, MA 02114 USA
关键词
LOCI; PHENOTYPES; RISK;
D O I
10.1093/bioinformatics/btr116
中图分类号
Q5 [生物化学];
学科分类号
071010 ; 081704 ;
摘要
Motivation: The concept of pleiotropy was proposed a century ago, though up to now there have been insufficient efforts to design robust statistics and software aimed at visualizing and evaluating pleiotropy at a regional level. The Pleiotropic Region Identification Method (PRIMe) was developed to evaluate potentially pleiotropic loci based upon data from multiple genome-wide association studies (GWAS). Methods: We first provide a software tool to systematically identify and characterize genomic regions where low association P-values are observed with multiple traits. We use the term Pleiotropy Index to denote the number of traits with low association P-values at a particular genomic region. For GWAS assumed to be uncorrelated, we adopted the binomial distribution to approximate the statistical significance of the Pleiotropy Index. For GWAS conducted on traits with known correlation coefficients, simulations are performed to derive the statistical distribution of the Pleiotropy Index under the null hypothesis of no genotype-phenotype association. For six hematologic and three blood pressure traits where full GWAS results were available from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, we estimated the trait correlations and applied the simulation approach to examine genomic regions with statistical evidence of pleiotropy. We then applied the approximation approach to explore GWAS summarized in the National Human Genome Research Institute (NHGRI) GWAS Catalog. Results: By simulation, we identified pleiotropic regions including SH2B3 and BRAP (12q24.12) for hematologic and blood pressure traits. By approximation, we confirmed the genome-wide significant pleiotropy of these two regions based on the GWAS Catalog data, together with an exploration on other regions which highlights the FTO, GCKR and ABO regions.
引用
收藏
页码:1201 / 1206
页数:6
相关论文
共 32 条
[1]   Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes [J].
Barrett, Jeffrey C. ;
Clayton, David G. ;
Concannon, Patrick ;
Akolkar, Beena ;
Cooper, Jason D. ;
Erlich, Henry A. ;
Julier, Cecile ;
Morahan, Grant ;
Nerup, Jorn ;
Nierras, Concepcion ;
Plagnol, Vincent ;
Pociot, Flemming ;
Schuilenburg, Helen ;
Smyth, Deborah J. ;
Stevens, Helen ;
Todd, John A. ;
Walker, Neil M. ;
Rich, Stephen S. .
NATURE GENETICS, 2009, 41 (06) :703-707
[2]   Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls [J].
Burton, Paul R. ;
Clayton, David G. ;
Cardon, Lon R. ;
Craddock, Nick ;
Deloukas, Panos ;
Duncanson, Audrey ;
Kwiatkowski, Dominic P. ;
McCarthy, Mark I. ;
Ouwehand, Willem H. ;
Samani, Nilesh J. ;
Todd, John A. ;
Donnelly, Peter ;
Barrett, Jeffrey C. ;
Davison, Dan ;
Easton, Doug ;
Evans, David ;
Leung, Hin-Tak ;
Marchini, Jonathan L. ;
Morris, Andrew P. ;
Spencer, Chris C. A. ;
Tobin, Martin D. ;
Attwood, Antony P. ;
Boorman, James P. ;
Cant, Barbara ;
Everson, Ursula ;
Hussey, Judith M. ;
Jolley, Jennifer D. ;
Knight, Alexandra S. ;
Koch, Kerstin ;
Meech, Elizabeth ;
Nutland, Sarah ;
Prowse, Christopher V. ;
Stevens, Helen E. ;
Taylor, Niall C. ;
Walters, Graham R. ;
Walker, Neil M. ;
Watkins, Nicholas A. ;
Winzer, Thilo ;
Jones, Richard W. ;
McArdle, Wendy L. ;
Ring, Susan M. ;
Strachan, David P. ;
Pembrey, Marcus ;
Breen, Gerome ;
St Clair, David ;
Caesar, Sian ;
Gordon-Smith, Katherine ;
Jones, Lisa ;
Fraser, Christine ;
Green, Elain K. .
NATURE, 2007, 447 (7145) :661-678
[3]   Overexpression of Fto leads to increased food intake and results in obesity [J].
Church, Chris ;
Moir, Lee ;
McMurray, Fiona ;
Girard, Christophe ;
Banks, Gareth T. ;
Teboul, Lydia ;
Wells, Sara ;
Bruening, Jens C. ;
Nolan, Patrick M. ;
Ashcroft, Frances M. ;
Cox, Roger D. .
NATURE GENETICS, 2010, 42 (12) :1086-U147
[4]   So many correlated tests, so little time!: Rapid adjustment of P values for multiple correlated tests [J].
Conneely, Karen N. ;
Boehnke, Michael .
AMERICAN JOURNAL OF HUMAN GENETICS, 2007, 81 (06) :1158-1168
[5]   Efficiency and power in genetic association studies [J].
de Bakker, PIW ;
Yelensky, R ;
Pe'er, I ;
Gabriel, SB ;
Daly, MJ ;
Altshuler, D .
NATURE GENETICS, 2005, 37 (11) :1217-1223
[6]   A multivariate test of association [J].
Ferreira, Manuel A. R. ;
Purcell, Shaun M. .
BIOINFORMATICS, 2009, 25 (01) :132-133
[7]   Pleiotropy as a mechanism to stabilize cooperation [J].
Foster, KR ;
Shaulsky, G ;
Strassmann, JE ;
Queller, DC ;
Thompson, CRL .
NATURE, 2004, 431 (7009) :693-696
[8]   A second generation human haplotype map of over 3.1 million SNPs [J].
Frazer, Kelly A. ;
Ballinger, Dennis G. ;
Cox, David R. ;
Hinds, David A. ;
Stuve, Laura L. ;
Gibbs, Richard A. ;
Belmont, John W. ;
Boudreau, Andrew ;
Hardenbol, Paul ;
Leal, Suzanne M. ;
Pasternak, Shiran ;
Wheeler, David A. ;
Willis, Thomas D. ;
Yu, Fuli ;
Yang, Huanming ;
Zeng, Changqing ;
Gao, Yang ;
Hu, Haoran ;
Hu, Weitao ;
Li, Chaohua ;
Lin, Wei ;
Liu, Siqi ;
Pan, Hao ;
Tang, Xiaoli ;
Wang, Jian ;
Wang, Wei ;
Yu, Jun ;
Zhang, Bo ;
Zhang, Qingrun ;
Zhao, Hongbin ;
Zhao, Hui ;
Zhou, Jun ;
Gabriel, Stacey B. ;
Barry, Rachel ;
Blumenstiel, Brendan ;
Camargo, Amy ;
Defelice, Matthew ;
Faggart, Maura ;
Goyette, Mary ;
Gupta, Supriya ;
Moore, Jamie ;
Nguyen, Huy ;
Onofrio, Robert C. ;
Parkin, Melissa ;
Roy, Jessica ;
Stahl, Erich ;
Winchester, Ellen ;
Ziaugra, Liuda ;
Altshuler, David ;
Shen, Yan .
NATURE, 2007, 449 (7164) :851-U3
[9]   Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium [J].
Ganesh, Santhi K. ;
Zakai, Neil A. ;
van Rooij, Frank J. A. ;
Soranzo, Nicole ;
Smith, Albert V. ;
Nalls, Michael A. ;
Chen, Ming-Huei ;
Kottgen, Anna ;
Glazer, Nicole L. ;
Dehghan, Abbas ;
Kuhnel, Brigitte ;
Aspelund, Thor ;
Yang, Qiong ;
Tanaka, Toshiko ;
Jaffe, Andrew ;
Bis, Joshua C. M. ;
Verwoert, Germaine C. ;
Teumer, Alexander ;
Fox, Caroline S. ;
Guralnik, Jack M. ;
Ehret, Georg B. ;
Rice, Kenneth ;
Felix, Janine F. ;
Rendon, Augusto ;
Eiriksdottir, Gudny ;
Levy, Daniel ;
Patel, Kushang V. ;
Boerwinkle, Eric ;
Rotter, Jerome I. ;
Hofman, Albert ;
Sambrook, Jennifer G. ;
Hernandez, Dena G. ;
Zheng, Gang ;
Bandinelli, Stefania ;
Singleton, Andrew B. ;
Coresh, Josef ;
Lumley, Thomas ;
Uitterlinden, Andre G. ;
vanGils, Janine M. ;
Launer, Lenore J. ;
Cupples, L. Adrienne ;
Oostra, Ben A. ;
Zwaginga, Jaap-Jan ;
Ouwehand, Willem H. ;
Thein, Swee-Lay ;
Meisinger, Christa ;
Deloukas, Panos ;
Nauck, Matthias ;
Spector, Tim D. ;
Gieger, Christian .
NATURE GENETICS, 2009, 41 (11) :1191-U48
[10]   Potential etiologic and functional implications of genome-wide association loci for human diseases and traits [J].
Hindorff, Lucia A. ;
Sethupathy, Praveen ;
Junkins, Heather A. ;
Ramos, Erin M. ;
Mehta, Jayashri P. ;
Collins, Francis S. ;
Manolio, Teri A. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2009, 106 (23) :9362-9367