MAGMA: Generalized Gene-Set Analysis of GWAS Data

被引:2029
作者
de Leeuw, Christiaan A. [1 ,2 ]
Mooij, Joris M. [3 ]
Heskes, Tom [2 ]
Posthuma, Danielle [1 ,4 ]
机构
[1] Vrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Dept Complex Trait Genet, Amsterdam, Netherlands
[2] Radboud Univ Nijmegen, Inst Comp & Informat Sci, NL-6525 ED Nijmegen, Netherlands
[3] Univ Amsterdam, Inst Informat, Amsterdam, Netherlands
[4] Vrije Univ Amsterdam, Med Ctr Amsterdam, Dept Clin Genet, Amsterdam, Netherlands
关键词
GENOME-WIDE ASSOCIATION; ENRICHMENT ANALYSIS; LOCI;
D O I
10.1371/journal.pcbi.1004219
中图分类号
Q5 [生物化学];
学科分类号
071010 ; 081704 ;
摘要
By aggregating data for complex traits in a biologically meaningful way, gene and gene-set analysis constitute a valuable addition to single-marker analysis. However, although various methods for gene and gene-set analysis currently exist, they generally suffer from a number of issues. Statistical power for most methods is strongly affected by linkage disequilibrium between markers, multi-marker associations are often hard to detect, and the reliance on permutation to compute p-values tends to make the analysis computationally very expensive. To address these issues we have developed MAGMA, a novel tool for gene and gene-set analysis. The gene analysis is based on a multiple regression model, to provide better statistical performance. The gene-set analysis is built as a separate layer around the gene analysis for additional flexibility. This gene-set analysis also uses a regression structure to allow generalization to analysis of continuous properties of genes and simultaneous analysis of multiple gene sets and other gene properties. Simulations and an analysis of Crohn's Disease data are used to evaluate the performance of MAGMA and to compare it to a number of other gene and gene-set analysis tools. The results show that MAGMA has significantly more power than other tools for both the gene and the gene-set analysis, identifying more genes and gene sets associated with Crohn's Disease while maintaining a correct type 1 error rate. Moreover, the MAGMA analysis of the Crohn's Disease data was found to be considerably faster as well.
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页数:19
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共 26 条
[1]   Hundreds of variants clustered in genomic loci and biological pathways affect human height [J].
Allen, Hana Lango ;
Estrada, Karol ;
Lettre, Guillaume ;
Berndt, Sonja I. ;
Weedon, Michael N. ;
Rivadeneira, Fernando ;
Willer, Cristen J. ;
Jackson, Anne U. ;
Vedantam, Sailaja ;
Raychaudhuri, Soumya ;
Ferreira, Teresa ;
Wood, Andrew R. ;
Weyant, Robert J. ;
Segre, Ayellet V. ;
Speliotes, Elizabeth K. ;
Wheeler, Eleanor ;
Soranzo, Nicole ;
Park, Ju-Hyun ;
Yang, Jian ;
Gudbjartsson, Daniel ;
Heard-Costa, Nancy L. ;
Randall, Joshua C. ;
Qi, Lu ;
Smith, Albert Vernon ;
Maegi, Reedik ;
Pastinen, Tomi ;
Liang, Liming ;
Heid, Iris M. ;
Luan, Jian'an ;
Thorleifsson, Gudmar ;
Winkler, Thomas W. ;
Goddard, Michael E. ;
Lo, Ken Sin ;
Palmer, Cameron ;
Workalemahu, Tsegaselassie ;
Aulchenko, Yurii S. ;
Johansson, Asa ;
Zillikens, M. Carola ;
Feitosa, Mary F. ;
Esko, Tonu ;
Johnson, Toby ;
Ketkar, Shamika ;
Kraft, Peter ;
Mangino, Massimo ;
Prokopenko, Inga ;
Absher, Devin ;
Albrecht, Eva ;
Ernst, Florian ;
Glazer, Nicole L. ;
Hayward, Caroline .
NATURE, 2010, 467 (7317) :832-838
[2]   An integrated map of genetic variation from 1,092 human genomes [J].
Altshuler, David M. ;
Durbin, Richard M. ;
Abecasis, Goncalo R. ;
Bentley, David R. ;
Chakravarti, Aravinda ;
Clark, Andrew G. ;
Donnelly, Peter ;
Eichler, Evan E. ;
Flicek, Paul ;
Gabriel, Stacey B. ;
Gibbs, Richard A. ;
Green, Eric D. ;
Hurles, Matthew E. ;
Knoppers, Bartha M. ;
Korbel, Jan O. ;
Lander, Eric S. ;
Lee, Charles ;
Lehrach, Hans ;
Mardis, Elaine R. ;
Marth, Gabor T. ;
McVean, Gil A. ;
Nickerson, Deborah A. ;
Schmidt, Jeanette P. ;
Sherry, Stephen T. ;
Wang, Jun ;
Wilson, Richard K. ;
Gibbs, Richard A. ;
Dinh, Huyen ;
Kovar, Christie ;
Lee, Sandra ;
Lewis, Lora ;
Muzny, Donna ;
Reid, Jeff ;
Wang, Min ;
Wang, Jun ;
Fang, Xiaodong ;
Guo, Xiaosen ;
Jian, Min ;
Jiang, Hui ;
Jin, Xin ;
Li, Guoqing ;
Li, Jingxiang ;
Li, Yingrui ;
Li, Zhuo ;
Liu, Xiao ;
Lu, Yao ;
Ma, Xuedi ;
Su, Zhe ;
Tai, Shuaishuai ;
Tang, Meifang .
NATURE, 2012, 491 (7422) :56-65
[3]   Integrating common and rare genetic variation in diverse human populations [J].
Altshuler, David M. ;
Gibbs, Richard A. ;
Peltonen, Leena ;
Dermitzakis, Emmanouil ;
Schaffner, Stephen F. ;
Yu, Fuli ;
Bonnen, Penelope E. ;
de Bakker, Paul I. W. ;
Deloukas, Panos ;
Gabriel, Stacey B. ;
Gwilliam, Rhian ;
Hunt, Sarah ;
Inouye, Michael ;
Jia, Xiaoming ;
Palotie, Aarno ;
Parkin, Melissa ;
Whittaker, Pamela ;
Chang, Kyle ;
Hawes, Alicia ;
Lewis, Lora R. ;
Ren, Yanru ;
Wheeler, David ;
Muzny, Donna Marie ;
Barnes, Chris ;
Darvishi, Katayoon ;
Hurles, Matthew ;
Korn, Joshua M. ;
Kristiansson, Kati ;
Lee, Charles ;
McCarroll, Steven A. ;
Nemesh, James ;
Keinan, Alon ;
Montgomery, Stephen B. ;
Pollack, Samuela ;
Price, Alkes L. ;
Soranzo, Nicole ;
Gonzaga-Jauregui, Claudia ;
Anttila, Verneri ;
Brodeur, Wendy ;
Daly, Mark J. ;
Leslie, Stephen ;
McVean, Gil ;
Moutsianas, Loukas ;
Nguyen, Huy ;
Zhang, Qingrun ;
Ghori, Mohammed J. R. ;
McGinnis, Ralph ;
McLaren, William ;
Takeuchi, Fumihiko ;
Grossman, Sharon R. .
NATURE, 2010, 467 (7311) :52-58
[4]   Data quality control in genetic case-control association studies [J].
Anderson, Carl A. ;
Pettersson, Fredrik H. ;
Clarke, Geraldine M. ;
Cardon, Lon R. ;
Morris, Andrew P. ;
Zondervan, Krina T. .
NATURE PROTOCOLS, 2010, 5 (09) :1564-1573
[5]   A review of major Crohn's disease susceptibility genes and their role in disease pathogenesis [J].
Barrett, Meghan ;
Chandra, Sathees B. .
GENES & GENOMICS, 2011, 33 (04) :317-325
[6]   METHOD FOR COMBINING NON-INDEPENDENT, ONE-SIDED TESTS OF SIGNIFICANCE [J].
BROWN, MB .
BIOMETRICS, 1975, 31 (04) :987-992
[7]   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
[8]   Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci [J].
Franke, Andre ;
McGovern, Dermot P. B. ;
Barrett, Jeffrey C. ;
Wang, Kai ;
Radford-Smith, Graham L. ;
Ahmad, Tariq ;
Lees, Charlie W. ;
Balschun, Tobias ;
Lee, James ;
Roberts, Rebecca ;
Anderson, Carl A. ;
Bis, Joshua C. ;
Bumpstead, Suzanne ;
Ellinghaus, David ;
Festen, Eleonora M. ;
Georges, Michel ;
Green, Todd ;
Haritunians, Talin ;
Jostins, Luke ;
Latiano, Anna ;
Mathew, Christopher G. ;
Montgomery, Grant W. ;
Prescott, Natalie J. ;
Raychaudhuri, Soumya ;
Rotter, Jerome I. ;
Schumm, Philip ;
Sharma, Yashoda ;
Simms, Lisa A. ;
Taylor, Kent D. ;
Whiteman, David ;
Wijmenga, Cisca ;
Baldassano, Robert N. ;
Barclay, Murray ;
Bayless, Theodore M. ;
Brand, Stephan ;
Buening, Carsten ;
Cohen, Albert ;
Colombel, Jean-Frederick ;
Cottone, Mario ;
Stronati, Laura ;
Denson, Ted ;
De Vos, Martine ;
D'Inca, Renata ;
Dubinsky, Marla ;
Edwards, Cathryn ;
Florin, Tim ;
Franchimont, Denis ;
Gearry, Richard ;
Glas, Juergen ;
Van Gossum, Andre .
NATURE GENETICS, 2010, 42 (12) :1118-+
[9]   Gene Ontology Analysis of GWA Study Data Sets Provides Insights into the Biology of Bipolar Disorder [J].
Holmans, Peter ;
Green, Elaine K. ;
Pahwa, Jaspreet Singh ;
Ferreira, Manuel A. R. ;
Purcell, Shaun M. ;
Sklar, Pamela ;
Owen, Michael J. ;
O'Donovan, Michael C. ;
Craddock, Nick .
AMERICAN JOURNAL OF HUMAN GENETICS, 2009, 85 (01) :13-24
[10]   A simple approximation for the distribution of the weighted combination of non-independent or independent probabilities [J].
Hou, CD .
STATISTICS & PROBABILITY LETTERS, 2005, 73 (02) :179-187