{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T19:26:14Z","timestamp":1774380374653,"version":"3.50.1"},"reference-count":128,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2016,10,2]],"date-time":"2016-10-02T00:00:00Z","timestamp":1475366400000},"content-version":"vor","delay-in-days":2461,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/2.0\/uk\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2010,2,15]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Motivation: The sequencing of the human genome has made it possible to identify an informative set of &amp;gt;1 million single nucleotide polymorphisms (SNPs) across the genome that can be used to carry out genome-wide association studies (GWASs). The availability of massive amounts of GWAS data has necessitated the development of new biostatistical methods for quality control, imputation and analysis issues including multiple testing. This work has been successful and has enabled the discovery of new associations that have been replicated in multiple studies. However, it is now recognized that most SNPs discovered via GWAS have small effects on disease susceptibility and thus may not be suitable for improving health care through genetic testing. One likely explanation for the mixed results of GWAS is that the current biostatistical analysis paradigm is by design agnostic or unbiased in that it ignores all prior knowledge about disease pathobiology. Further, the linear modeling framework that is employed in GWAS often considers only one SNP at a time thus ignoring their genomic and environmental context. There is now a shift away from the biostatistical approach toward a more holistic approach that recognizes the complexity of the genotype\u2013phenotype relationship that is characterized by significant heterogeneity and gene\u2013gene and gene\u2013environment interaction. We argue here that bioinformatics has an important role to play in addressing the complexity of the underlying genetic basis of common human diseases. The goal of this review is to identify and discuss those GWAS challenges that will require computational methods.<\/jats:p><jats:p>Contact: \u00a0jason.h.moore@dartmouth.edu<\/jats:p>","DOI":"10.1093\/bioinformatics\/btp713","type":"journal-article","created":{"date-parts":[[2010,1,7]],"date-time":"2010-01-07T02:54:39Z","timestamp":1262832879000},"page":"445-455","source":"Crossref","is-referenced-by-count":453,"title":["Bioinformatics challenges for genome-wide association studies"],"prefix":"10.1093","volume":"26","author":[{"given":"Jason H.","family":"Moore","sequence":"first","affiliation":[{"name":"1 Department of Genetics, 2 Department of Community and Family Medicine, Dartmouth Medical School, Lebanon, NH 03756, USA, 3 Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands and 4 Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA"},{"name":"1 Department of Genetics, 2 Department of Community and Family Medicine, Dartmouth Medical School, Lebanon, NH 03756, USA, 3 Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands and 4 Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA"}]},{"given":"Folkert W.","family":"Asselbergs","sequence":"additional","affiliation":[{"name":"1 Department of Genetics, 2 Department of Community and Family Medicine, Dartmouth Medical School, Lebanon, NH 03756, USA, 3 Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands and 4 Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA"}]},{"given":"Scott M.","family":"Williams","sequence":"additional","affiliation":[{"name":"1 Department of Genetics, 2 Department of Community and Family Medicine, Dartmouth Medical School, Lebanon, NH 03756, USA, 3 Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands and 4 Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA"}]}],"member":"286","published-online":{"date-parts":[[2010,1,6]]},"reference":[{"key":"2023012508021565800_B1","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1038\/ng.354","article-title":"Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2","volume":"41","author":"Ahmed","year":"2009","journal-title":"Nat. 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Invest."},{"key":"2023012508021565800_B60","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1038\/nature08494","article-title":"Finding the missing heritability of complex diseases","volume":"461","author":"Manolio","year":"2009","journal-title":"Nature"},{"key":"2023012508021565800_B61","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1038\/ng1537","article-title":"Genome-wide strategies for detecting multiple loci that influence complex diseases","volume":"37","author":"Marchini","year":"2005","journal-title":"Nat. Genet."},{"key":"2023012508021565800_B62","doi-asserted-by":"crossref","first-page":"77","DOI":"10.2165\/00822942-200605020-00002","article-title":"Machine learning for detecting gene-gene interactions: a review","volume":"5","author":"McKinney","year":"2006","journal-title":"Appl. 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Genet."},{"key":"2023012508021565800_B102","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1086\/321276","article-title":"Multifactor dimensionality reduction reveals high-order interactions among estrogen metabolism genes in sporadic breast cancer","volume":"69","author":"Ritchie","year":"2001","journal-title":"Am. J. Hum. Genet."},{"key":"2023012508021565800_B103","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1002\/gepi.10218","article-title":"Power of multifactor dimensionality reduction for detecting gene-gene interactions in the presence of genotyping error, phenocopy, and genetic heterogeneity","volume":"24","author":"Ritchie","year":"2003","journal-title":"Genet. 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Polymorphisms in DNA repair genes, smoking and bladder cancer risk: findings from the international consortium of bladder cancer","volume":"69","author":"Stern","year":"2009","journal-title":"Cancer Res."},{"key":"2023012508021565800_B111","doi-asserted-by":"crossref","first-page":"S62","DOI":"10.1186\/1753-6561-1-S1-S62","article-title":"Classification of rheumatoid arthritis status with candidate gene and genome-wide single-nucleotide polymorphisms using random forests","volume":"1","author":"Sun","year":"2007","journal-title":"BMC Proc."},{"key":"2023012508021565800_B112","first-page":"41","article-title":"Epistasis and complex traits","volume-title":"Epistasis and the Evolutionary Process.","author":"Templeton","year":"2000"},{"key":"2023012508021565800_B113","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1038\/nature04226","article-title":"A haplotype map of the human genome","volume":"437","author":"The International HapMap Consortium","year":"2005","journal-title":"Nature"},{"key":"2023012508021565800_B114","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1016\/j.tig.2004.09.007","article-title":"Genetics, statistics and human disease: analytical retooling for complexity","volume":"20","author":"Thornton-Wells","year":"2004","journal-title":"Trends Genet."},{"key":"2023012508021565800_B115","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.ygeno.2008.07.011","article-title":"Pathway analysis of seven common diseases assessed by genome-wide association","volume":"92","author":"Torkamani","year":"2008","journal-title":"Genomics"},{"key":"2023012508021565800_B116","doi-asserted-by":"crossref","first-page":"1314","DOI":"10.1093\/bioinformatics\/btp158","article-title":"Evaluation of genome-wide association study results through development of ontology fingerprints","volume":"25","author":"Tsoi","year":"2009","journal-title":"Bioinformatics"},{"key":"2023012508021565800_B117","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1002\/gepi.20211","article-title":"A balanced accuracy metric for epistasis modeling in imbalanced datasets using multifactor dimensionality reduction","volume":"31","author":"Velez","year":"2007","journal-title":"Genet. 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