{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T13:29:36Z","timestamp":1768915776506,"version":"3.49.0"},"reference-count":42,"publisher":"Springer Science and Business Media LLC","issue":"1","content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Bioinformatics"],"published-print":{"date-parts":[[2011,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Single Nucleotide Polymorphism (SNP) analysis only captures a small proportion of associated genetic variants in Genome-Wide Association Studies (GWAS) partly due to small marginal effects. Pathway level analysis incorporating prior biological information offers another way to analyze GWAS's of complex diseases, and promises to reveal the mechanisms leading to complex diseases. Biologically defined pathways are typically comprised of numerous genes. If only a subset of genes in the pathways is associated with disease then a joint analysis including all individual genes would result in a loss of power. To address this issue, we propose a pathway-based method that allows us to test for joint effects by using a pre-selected gene subset. In the proposed approach, each gene is considered as the basic unit, which reduces the number of genetic variants considered and hence reduces the degrees of freedom in the joint analysis. The proposed approach also can be used to investigate the joint effect of several genes in a candidate gene study.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We applied this new method to a published GWAS of psoriasis and identified 6 biologically plausible pathways, after adjustment for multiple testing. The pathways identified in our analysis overlap with those reported in previous studies. Further, using simulations across a range of gene numbers and effect sizes, we demonstrate that the proposed approach enjoys higher power than several other approaches to detect associated pathways.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The proposed method could increase the power to discover susceptibility pathways and to identify associated genes using GWAS. In our analysis of genome-wide psoriasis data, we have identified a number of relevant pathways for psoriasis.<\/jats:p><\/jats:sec>","DOI":"10.1186\/1471-2105-12-17","type":"journal-article","created":{"date-parts":[[2011,1,19]],"date-time":"2011-01-19T11:09:01Z","timestamp":1295435341000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Pathway-based analysis using reduced gene subsets in genome-wide association studies"],"prefix":"10.1186","volume":"12","author":[{"given":"Jingyuan","family":"Zhao","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simone","family":"Gupta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"Seielstad","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianjun","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anbupalam","family":"Thalamuthu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2011,1,12]]},"reference":[{"issue":"2","key":"4334_CR1","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1038\/nrg1270","volume":"5","author":"KT Zondervan","year":"2004","unstructured":"Zondervan KT, Cardon LR: The complex interplay among factors that influence allelic association. Nat Rev Genet 2004, 5(2):89\u2013100. 10.1038\/nrg1270","journal-title":"Nat Rev Genet"},{"issue":"5","key":"4334_CR2","doi-asserted-by":"publisher","first-page":"780","DOI":"10.1086\/429838","volume":"76","author":"DJ Schaid","year":"2005","unstructured":"Schaid DJ, McDonnell SK, Hebbring SJ, Cunningham JM, Thibodeau SN: Nonparametric tests of association of multiple genes with human disease. Am J Hum Genet 2005, 76(5):780\u2013793. 10.1086\/429838","journal-title":"Am J Hum Genet"},{"issue":"9","key":"4334_CR3","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1038\/nrg1155","volume":"4","author":"J Hoh","year":"2003","unstructured":"Hoh J, Ott J: Mathematical multi-locus approaches to localizing complex human trait genes. Nature Reviews Genetics 2003, 4(9):701\u2013709. 10.1038\/nrg1155","journal-title":"Nature Reviews Genetics"},{"issue":"2","key":"4334_CR4","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1002\/gepi.0042","volume":"22","author":"DV Zaykin","year":"2002","unstructured":"Zaykin DV, Zhivotovsky LA, Westfall PH, Weir BS: Truncated product method for combining P-values. Genetic Epidemiology 2002, 22(2):170\u2013185. 10.1002\/gepi.0042","journal-title":"Genetic Epidemiology"},{"issue":"4","key":"4334_CR5","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1002\/gepi.10264","volume":"25","author":"F Dudbridge","year":"2003","unstructured":"Dudbridge F, Koeleman BPC: Rank truncated product of P-values, with application to genomewide association scans. Genetic Epidemiology 2003, 25(4):360\u2013366. 10.1002\/gepi.10264","journal-title":"Genetic Epidemiology"},{"issue":"3","key":"4334_CR6","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1002\/gepi.20452","volume":"34","author":"O De la Cruz","year":"2010","unstructured":"De la Cruz O, Wen X, Ke B, Song M, Nicolae DL: Gene, region and pathway level analyses in whole-genome studies. Genet Epidemiol 2010, 34(3):222\u2013231.","journal-title":"Genet Epidemiol"},{"issue":"9","key":"4334_CR7","doi-asserted-by":"publisher","first-page":"1950","DOI":"10.1093\/bioinformatics\/bti267","volume":"21","author":"JJ Goeman","year":"2005","unstructured":"Goeman JJ, Oosting J, Cleton-Jansen AM, Anninga JK, van Houwelingen HC: Testing association of a pathway with survival using gene expression data. Bioinformatics 2005, 21(9):1950\u20131957. 10.1093\/bioinformatics\/bti267","journal-title":"Bioinformatics"},{"issue":"7","key":"4334_CR8","doi-asserted-by":"publisher","first-page":"636","DOI":"10.1002\/gepi.20175","volume":"30","author":"J Tyrer","year":"2006","unstructured":"Tyrer J, Pharoah PD, Easton DF: The admixture maximum likelihood test: a novel experiment-wise test of association between disease and multiple SNPs. Genet Epidemiol 2006, 30(7):636\u2013643. 10.1002\/gepi.20175","journal-title":"Genet Epidemiol"},{"issue":"4","key":"4334_CR9","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1093\/bioinformatics\/btn641","volume":"25","author":"M Li","year":"2009","unstructured":"Li M, Wang K, Grant SF, Hakonarson H, Li C: ATOM: a powerful gene-based association test by combining optimally weighted markers. Bioinformatics 2009, 25(4):497\u2013503. 10.1093\/bioinformatics\/btn641","journal-title":"Bioinformatics"},{"issue":"3","key":"4334_CR10","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1002\/gepi.20448","volume":"34","author":"DH Ballard","year":"2010","unstructured":"Ballard DH, Cho J, Zhao H: Comparisons of multi-marker association methods to detect association between a candidate region and disease. Genet Epidemiol 2010, 34(3):201\u2013212. 10.1002\/gepi.20448","journal-title":"Genet Epidemiol"},{"issue":"5","key":"4334_CR11","doi-asserted-by":"publisher","first-page":"792","DOI":"10.1086\/508346","volume":"79","author":"J Wessel","year":"2006","unstructured":"Wessel J, Schork NJ: Generalized genomic distance-based regression methodology for multilocus association analysis. Am J Hum Genet 2006, 79(5):792\u2013806. 10.1086\/508346","journal-title":"Am J Hum Genet"},{"issue":"3","key":"4334_CR12","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1002\/gepi.20451","volume":"34","author":"I Mukhopadhyay","year":"2010","unstructured":"Mukhopadhyay I, Feingold E, Weeks DE, Thalamuthu A: Association tests using kernel-based measures of multi-locus genotype similarity between individuals. Genet Epidemiol 2010, 34(3):213\u2013221.","journal-title":"Genet Epidemiol"},{"issue":"8","key":"4334_CR13","doi-asserted-by":"publisher","first-page":"618","DOI":"10.1038\/nrg1407","volume":"5","author":"O Carlborg","year":"2004","unstructured":"Carlborg O, Haley CS: Epistasis: too often neglected in complex trait studies? Nat Rev Genet 2004, 5(8):618\u2013625. 10.1038\/nrg1407","journal-title":"Nat Rev Genet"},{"issue":"7","key":"4334_CR14","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1002\/gepi.20334","volume":"32","author":"DI Chasman","year":"2008","unstructured":"Chasman DI: On the utility of gene set methods in genomewide association studies of quantitative traits. Genet Epidemiol 2008, 32(7):658\u2013668. 10.1002\/gepi.20334","journal-title":"Genet Epidemiol"},{"issue":"6","key":"4334_CR15","doi-asserted-by":"publisher","first-page":"1278","DOI":"10.1086\/522374","volume":"81","author":"K Wang","year":"2007","unstructured":"Wang K, Li M, Bucan M: Pathway-Based Approaches for Analysis of Genomewide Association Studies. Am J Hum Genet 2007, 81(6):1278\u20131283. 10.1086\/522374","journal-title":"Am J Hum Genet"},{"issue":"20","key":"4334_CR16","doi-asserted-by":"publisher","first-page":"2762","DOI":"10.1093\/bioinformatics\/btp448","volume":"25","author":"C O'Dushlaine","year":"2009","unstructured":"O'Dushlaine C, Kenny E, Heron EA, Segurado R, Gill M, Morris DW, Corvin A: The SNP ratio test: pathway analysis of genome-wide association datasets. Bioinformatics 2009, 25(20):2762\u20132763.","journal-title":"Bioinformatics"},{"issue":"2","key":"4334_CR17","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1093\/bioinformatics\/btn613","volume":"25","author":"L Chen","year":"2009","unstructured":"Chen L, Zhang L, Zhao Y, Xu L, Shang Y, Wang Q, Li W, Wang H, Li X: Prioritizing risk pathways: a novel association approach to searching for disease pathways fusing SNPs and pathways. Bioinformatics 2009, 25(2):237\u2013242. 10.1093\/bioinformatics\/btn613","journal-title":"Bioinformatics"},{"issue":"3","key":"4334_CR18","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1086\/423738","volume":"75","author":"F Dudbridge","year":"2004","unstructured":"Dudbridge F, Koeleman BP: Efficient computation of significance levels for multiple associations in large studies of correlated data, including genomewide association studies. Am J Hum Genet 2004, 75(3):424\u2013435. 10.1086\/423738","journal-title":"Am J Hum Genet"},{"issue":"8","key":"4334_CR19","doi-asserted-by":"publisher","first-page":"700","DOI":"10.1002\/gepi.20422","volume":"33","author":"K Yu","year":"2009","unstructured":"Yu K, Li Q, Bergen AW, Pfeiffer RM, Rosenberg PS, Caporaso N, Kraft P, Chatterjee N: Pathway analysis by adaptive combination of P-values. Genet Epidemiol 2009, 33(8):700\u2013709. 10.1002\/gepi.20422","journal-title":"Genet Epidemiol"},{"issue":"11","key":"4334_CR20","doi-asserted-by":"publisher","first-page":"e8068","DOI":"10.1371\/journal.pone.0008068","volume":"4","author":"H Eleftherohorinou","year":"2009","unstructured":"Eleftherohorinou H, Wright V, Hoggart C, Hartikainen AL, Jarvelin MR, Balding D, Coin L, Levin M: Pathway analysis of GWAS provides new insights into genetic susceptibility to 3 inflammatory diseases. PLoS One 2009, 4(11):e8068. 10.1371\/journal.pone.0008068","journal-title":"PLoS One"},{"issue":"9","key":"4334_CR21","doi-asserted-by":"publisher","first-page":"1045","DOI":"10.1038\/ejhg.2010.62","volume":"18","author":"L Luo","year":"2010","unstructured":"Luo L, Peng G, Zhu Y, Dong H, Amos CI, Xiong M: Genome-wide gene and pathway analysis. Eur J Hum Genet 2010, 18(9):1045\u20131053. 10.1038\/ejhg.2010.62","journal-title":"Eur J Hum Genet"},{"issue":"1","key":"4334_CR22","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1016\/j.ajhg.2009.11.017","volume":"86","author":"RM Cantor","year":"2010","unstructured":"Cantor RM, Lange K, Sinsheimer JS, Prioritizing GWAS results: A review of statistical methods and recommendations for their application. Am J Hum Genet 2010, 86(1):6\u201322. 10.1016\/j.ajhg.2009.11.017","journal-title":"Am J Hum Genet"},{"issue":"5","key":"4334_CR23","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1002\/gepi.20395","volume":"33","author":"CC Elbers","year":"2009","unstructured":"Elbers CC, van Eijk KR, Franke L, Mulder F, van der Schouw YT, Wijmenga C, Onland-Moret NC: Using genome-wide pathway analysis to unravel the etiology of complex diseases. Genet Epidemiol 2009, 33(5):419\u2013431. 10.1002\/gepi.20395","journal-title":"Genet Epidemiol"},{"key":"4334_CR24","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1111\/j.2517-6161.1996.tb02080.x","volume":"58","author":"R Tibshirani","year":"1996","unstructured":"Tibshirani R: Regression shrinkage and selection via the LASSO. Journal of the Royal Statistical Society: Series B (Statistical Methodology) 1996, 58: 267\u2013288.","journal-title":"Journal of the Royal Statistical Society: Series B (Statistical Methodology)"},{"key":"4334_CR25","volume-title":"Principal Component Analysis","author":"I Jolliffe","year":"2002","unstructured":"Jolliffe I: Principal Component Analysis. New York: Springer; 2002."},{"issue":"2","key":"4334_CR26","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1002\/gepi.20266","volume":"32","author":"K Wang","year":"2008","unstructured":"Wang K, Abbott D: A principal components regression approach to multilocus genetic association studies. Genet Epidemiol 2008, 32(2):108\u2013118. 10.1002\/gepi.20266","journal-title":"Genet Epidemiol"},{"issue":"9","key":"4334_CR27","doi-asserted-by":"publisher","first-page":"1164","DOI":"10.1093\/bioinformatics\/btm069","volume":"23","author":"W Stacklies","year":"2007","unstructured":"Stacklies W, Redestig H, Scholz M, Walther D, Selbig J: pcaMethods--a bioconductor package providing PCA methods for incomplete data. Bioinformatics 2007, 23(9):1164\u20131167. 10.1093\/bioinformatics\/btm069","journal-title":"Bioinformatics"},{"issue":"3","key":"4334_CR28","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1086\/519795","volume":"81","author":"S Purcell","year":"2007","unstructured":"Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, et al.: PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007, 81(3):559\u2013575. 10.1086\/519795","journal-title":"Am J Hum Genet"},{"issue":"2","key":"4334_CR29","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1038\/ng.311","volume":"41","author":"RP Nair","year":"2009","unstructured":"Nair RP, Duffin KC, Helms C, Ding J, Stuart PE, Goldgar D, Gudjonsson JE, Li Y, Tejasvi T, Feng BJ, et al.: Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways. Nat Genet 2009, 41(2):199\u2013204. 10.1038\/ng.311","journal-title":"Nat Genet"},{"issue":"8","key":"4334_CR30","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1007\/s00403-007-0775-4","volume":"299","author":"SP Jariwala","year":"2007","unstructured":"Jariwala SP: The role of dendritic cells in the immunopathogenesis of psoriasis. Arch Dermatol Res 2007, 299(8):359\u2013366. 10.1007\/s00403-007-0775-4","journal-title":"Arch Dermatol Res"},{"issue":"5","key":"4334_CR31","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1016\/j.ygeno.2008.07.011","volume":"92","author":"A Torkamani","year":"2008","unstructured":"Torkamani A, Topol EJ, Schork NJ: Pathway analysis of seven common diseases assessed by genome-wide association. Genomics 2008, 92(5):265\u2013272. 10.1016\/j.ygeno.2008.07.011","journal-title":"Genomics"},{"issue":"5","key":"4334_CR32","doi-asserted-by":"publisher","first-page":"P3","DOI":"10.1186\/gb-2003-4-5-p3","volume":"4","author":"G Dennis Jr","year":"2003","unstructured":"Dennis G Jr, Sherman BT, Hosack DA, Yang J, Gao W, Lane HC, Lempicki RA: DAVID: Database for Annotation, Visualization, and Integrated Discovery. Genome Biol 2003, 4(5):P3. 10.1186\/gb-2003-4-5-p3","journal-title":"Genome Biol"},{"issue":"29","key":"4334_CR33","doi-asserted-by":"publisher","first-page":"26333","DOI":"10.1074\/jbc.M303076200","volume":"278","author":"M Benezra","year":"2003","unstructured":"Benezra M, Chevallier N, Morrison DJ, MacLachlan TK, El-Deiry WS, Licht JD: BRCA1 augments transcription by the NF-kappaB transcription factor by binding to the Rel domain of the p65\/RelA subunit. J Biol Chem 2003, 278(29):26333\u201326341. 10.1074\/jbc.M303076200","journal-title":"J Biol Chem"},{"issue":"3-4","key":"4334_CR34","doi-asserted-by":"publisher","first-page":"427","DOI":"10.3109\/08830189809043004","volume":"16","author":"G Del Prete","year":"1998","unstructured":"Del Prete G: The concept of type-1 and type-2 helper T cells and their cytokines in humans. Int Rev Immunol 1998, 16(3\u20134):427\u2013455. 10.3109\/08830189809043004","journal-title":"Int Rev Immunol"},{"issue":"5488","key":"4334_CR35","doi-asserted-by":"publisher","first-page":"2350","DOI":"10.1126\/science.289.5488.2350","volume":"289","author":"EG Lee","year":"2000","unstructured":"Lee EG, Boone DL, Chai S, Libby SL, Chien M, Lodolce JP, Ma A: Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice. Science 2000, 289(5488):2350\u20132354. 10.1126\/science.289.5488.2350","journal-title":"Science"},{"issue":"3","key":"4334_CR36","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1038\/79734","volume":"1","author":"M Moser","year":"2000","unstructured":"Moser M, Murphy KM: Dendritic cell regulation of TH1-TH2 development. Nat Immunol 2000, 1(3):199\u2013205. 10.1038\/79734","journal-title":"Nat Immunol"},{"issue":"1","key":"4334_CR37","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1172\/JCI117308","volume":"94","author":"FO Nestle","year":"1994","unstructured":"Nestle FO, Turka LA, Nickoloff BJ: Characterization of dermal dendritic cells in psoriasis. Autostimulation of T lymphocytes and induction of Th1 type cytokines. J Clin Invest 1994, 94(1):202\u2013209. 10.1172\/JCI117308","journal-title":"J Clin Invest"},{"issue":"6","key":"4334_CR38","doi-asserted-by":"publisher","first-page":"871","DOI":"10.1001\/archderm.1991.01680050115015","volume":"127","author":"BJ Nickoloff","year":"1991","unstructured":"Nickoloff BJ: The cytokine network in psoriasis. Arch Dermatol 1991, 127(6):871\u2013884. 10.1001\/archderm.127.6.871","journal-title":"Arch Dermatol"},{"issue":"3","key":"4334_CR39","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1038\/gene.2009.11","volume":"10","author":"JT Elder","year":"2009","unstructured":"Elder JT: Genome-wide association scan yields new insights into the immunopathogenesis of psoriasis. Genes Immun 2009, 10(3):201\u2013209. 10.1038\/gene.2009.11","journal-title":"Genes Immun"},{"issue":"11","key":"4334_CR40","doi-asserted-by":"publisher","first-page":"3136","DOI":"10.2337\/db07-1731","volume":"57","author":"KJ Gaulton","year":"2008","unstructured":"Gaulton KJ, Willer CJ, Li Y, Scott LJ, Conneely KN, Jackson AU, Duren WL, Chines PS, Narisu N, Bonnycastle LL, et al.: Comprehensive association study of type 2 diabetes and related quantitative traits with 222 candidate genes. Diabetes 2008, 57(11):3136\u20133144. 10.2337\/db07-1731","journal-title":"Diabetes"},{"issue":"23","key":"4334_CR41","doi-asserted-by":"publisher","first-page":"9758","DOI":"10.1073\/pnas.0703736104","volume":"104","author":"RS Huang","year":"2007","unstructured":"Huang RS, Duan S, Bleibel WK, Kistner EO, Zhang W, Clark TA, Chen TX, Schweitzer AC, Blume JE, Cox NJ, et al.: A genome-wide approach to identify genetic variants that contribute to etoposide-induced cytotoxicity. Proc Natl Acad Sci USA 2007, 104(23):9758\u20139763. 10.1073\/pnas.0703736104","journal-title":"Proc Natl Acad Sci USA"},{"issue":"1","key":"4334_CR42","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1214\/07-AOAS101","volume":"1","author":"B Efron","year":"2007","unstructured":"Efron B, Tibshirani R: On testing the significance of sets of genes. The Annals of Applied Statistics 2007, 1(1):107\u2013129. 10.1214\/07-AOAS101","journal-title":"The Annals of Applied Statistics"}],"container-title":["BMC Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1471-2105-12-17.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,1]],"date-time":"2025-03-01T22:51:04Z","timestamp":1740869464000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcbioinformatics.biomedcentral.com\/articles\/10.1186\/1471-2105-12-17"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,1,12]]},"references-count":42,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2011,12]]}},"alternative-id":["4334"],"URL":"https:\/\/doi.org\/10.1186\/1471-2105-12-17","relation":{},"ISSN":["1471-2105"],"issn-type":[{"value":"1471-2105","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,1,12]]},"assertion":[{"value":"3 July 2010","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 January 2011","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 January 2011","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"17"}}