Abstract
The genome-wide association approach has been the most powerful and efficient study design thus far in identifying genetic variants that are associated with complex human diseases. This approach became feasible as the result of several key advancements in genetic knowledge, genotyping technologies, statistical analysis algorithms and the availability of large collections of cases and controls. With all these necessary tools in hand, many genome-wide association studies were recently completed, and many more studies which will explore the genetic basis of various complex diseases and quantitative traits are soon to come. This approach has started to reap the fruits of its labor over the past several months. Publications of genome-wide association studies in several complex diseases such as inflammatory bowel disease, type-2 diabetes, breast cancer and prostate cancer have been abundant in the first half of this year. The aims of this review are firstly, to provide a timely summary for most of the genome-wide association studies that have been published until June/July 2007 and secondly, to evaluate to what extent these results have been validated in subsequent replication studies.
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References
Risch N, Merikangas K : The future of genetic studies of complex human diseases. Science 1996; 273: 1516–1517.
International Human Genome Sequencing Consortium: Initial sequencing and analysis of the human genome. Nature 2001; 409: 860–921.
Venter JC, Adams MD, Myers EW et al: The sequence of the human genome. Science 2001; 291: 1304–1351.
Watson JD, Crick FH : Molecular structure of nucleic acids; a structure for deoxyribose nucleic acid. Nature 1953; 171: 737–738.
International Human Genome Sequencing Consortium: Finishing the euchromatic sequence of the human genome. Nature 2004; 431: 931–945.
International SNP Map Working Group: A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature 2001; 409: 928–933.
Sebat J, Lakshmi B, Troge J et al: Large-scale copy number polymorphism in the human genome. Science 2004; 305: 525–528.
Iafrate AJ, Feuk L, Rivera MN et al: Detection of large-scale variation in the human genome. Nat Genet 2004; 36: 949–951.
Redon R, Ishikawa S, Fitch KR et al: Global variation in copy number in the human genome. Nature 2006; 444: 444–454.
Feuk L, Carson AR, Scherer SW : Structural variation in the human genome. Nat Rev Genet 2006; 7: 85–97.
Stranger BE, Forrest MS, Dunning M et al: Relative impact of nucleotide and copy number variation on gene expression phenotypes. Science 2007; 315: 848–853.
Fanciulli M, Norsworthy PJ, Petretto E et al: FCGR3B copy number variation is associated with susceptibility to systemic, but not organ-specific, autoimmunity. Nat Genet 2007; 39: 721–723.
Yang Y, Chung EK, Wu YL et al: Gene copy-number variation and associated polymorphisms of complement component C4 in human systemic lupus erythematosus (SLE). Am J Hum Genet 2007; 80: 1037–1054.
Sebat J, Lakshmi B, Malhotra D et al: Strong association of de novo copy number mutations with autism. Science 2007; 316: 445–449.
Lachman HM, Pedrosa E, Petruolo OA et al: Increase in GSK3beta gene copy number variation in bipolar disorder. Am J Med Genet B Neuropsychiatr Genet 2007; 144: 259–265.
The International HapMap Consortium: The international HapMap project. Nature 2003; 426: 789–796.
The International HapMap Consortium: A haplotype map of the human genome. Nature 2005; 437: 1299–1320.
The International HapMap Consortium: A second generation human haplotype map of over 3.1 million SNPs. Nature 2007; 449: 851–861.
de Bakker PI, Burtt NP, Graham RR et al: Transferability of tag SNPs in genetic association studies in multiple populations. Nat Genet 2006; 38: 1298–1303.
Conrad DF, Jakobsson M, Coop G et al: A worldwide survey of haplotype variation and linkage disequilibrium in the human genome. Nat Genet 2006; 38: 1251–1260.
Bonnen PE, Pe’er I, Plenge RM et al: Evaluating potential for whole genome studies in Kosrae, an isolated population in Micronesia. Nat Genet 2006; 38: 214–217.
Service S, International Collaborative Group on Isolated Populations, Sabatti C, Freimer N : Tag SNPs chosen from HapMap perform well in several population isolates. Genet Epidemiol 2007; 31: 189–194.
Hinds DA, Stuve LL, Nilsen GB et al: Whole-genome patterns of common DNA variation in three human populations. Science 2005; 307: 1072–1079.
Wang WY, Barratt BJ, Clayton DG, Todd JA : Genome-wide association studies: theoretical and practical concerns. Nat Rev Genet 2005; 6: 109–118.
Hirschhorn JN, Daly MJ : Genome-wide association studies for common diseases and complex traits. Nat Rev Genet 2005; 6: 95–108.
Gunderson KL, Steemers FJ, Lee G, Mendoza LG, Chee MS : A genome-wide scalable SNP genotyping assay using microarray technology. Nat Genet 2005; 37: 549–554.
Steemers FJ, Gunderson KL : Whole genome genotyping technologies on the BeadArray platform. Biotechnol J 2007; 2: 41–49.
Kennedy GC, Matsuzaki H, Dong S et al: Large-scale genotyping of complex DNA. Nat Biotechnol 2003; 21: 1233–1237.
Barrett JC, Cardon LR : Evaluating coverage of genome-wide association studies. Nat Genet 2006; 38: 659–662.
Eberle MA, Ng PC, Kuhn K et al: Power to detect risk alleles using genome-wide tag SNP panels. PLoS Genet 2007; 3: 1827–1837.
Purcell S, Neale B, Todd-Brown K et al: PLINK: a toolset for whole genome association and population based linkage analyses. Am J Hum Genet 2007; 81: 559–575.
Bentley DR : Whole-genome re-sequencing. Curr Opin Genet Dev 2006; 16: 545–552.
Klein RJ, Zeiss C, Chew EY et al: Complement factor H polymorphism in age-related macular degeneration. Science 2005; 308: 385–389.
DeWan A, Liu M, Hartman S et al: HTRA1 promoter polymorphism in wet age-related macular degeneration. Science 2006; 314: 989–992.
Herbert A, Gerry NP, McQueen MB et al: A common genetic variant is associated with adult and childhood obesity. Science 2006; 312: 279–283.
Frayling TM, Timpson NJ, Weedon MN et al: A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 2007; 316: 889–894.
The Wellcome Trust Case Control Consortium: Genome-wide association study of 14 000 cases of seven common diseases and 3000 shared controls. Nature 2007; 447: 661–678.
Hugot JP, Chamaillard M, Zouali H et al: Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 2001; 411: 599–603.
Rioux JD, Daly MJ, Silverberg MS et al: Genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohn disease. Nat Genet 2001; 29: 223–228.
Duerr RH, Taylor KD, Brant SR et al: A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 2006; 314: 1461–1463.
Rioux JD, Xavier RJ, Taylor KD et al: Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat Genet 2007; 39: 596–604.
Libioulle C, Louis E, Hansoul S et al: Novel Crohn disease locus identified by genome-wide association maps to a gene desert on 5p13.1 and modulates expression of PTGER4. PLoS Genet 2007; 3: e58.
Parkes M, Barrett JC, Prescott NJ et al: Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility. Nat Genet 2007; 39: 830–832.
Altshuler D, Hirschhorn JN, Klannemark M et al: The common PPARγ Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet 2000; 26: 76–80.
Gloyn AL, Weedon MN, Owen KR et al: Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and ABCC8 confirm that the KCNJ11 E23K variant is associated with type-2 diabetes. Diabetes 2006; 52: 568–572.
Grant SF, Thorleifsson G, Reynisdottir I et al: Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet 2006; 38: 320–323.
Sladek R, Rocheleau G, Rung J et al: A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 2007; 445: 881–885.
Zeggini E, Weedon MN, Lindgren CM et al: Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 2007; 316: 1336–1341.
Diabetes Genetic Initiative (DGI) of Broad Institute of Harvard and MIT, Lund University and Novartis Institute for Biomedical Research: Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 2007; 316: 1331–1336.
Scott LJ, Mohlke KL, Bonnycastle LL et al: A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 2007; 316: 1341–1345.
Steinthorsdottir V, Thorleifsson G, Reynisdottir I et al: A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nat Genet 2007; 39: 770–775.
Easton DF, Pooley KA, Dunning AM et al: Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 2007; 447: 1087–1093.
Hunter DJ, Kraft P, Jacobs KB et al: A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet 2007; 39: 870–874.
Stacey SN, Manolescu A, Sulem P et al: Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet 2007; 39: 865–869.
Gudmundsson J, Sulem P, Manolescu A et al: Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24. Nat Genet 2007; 39: 631–637.
Yeager M, Orr N, Hayes RB et al: Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nat Genet 2007; 39: 645–649.
NCI-NHGRI Working Group on Replication in Association Studies: Replicating genotype-phenotype associations. Nature 2007; 447: 655–660.
Haines JL, Hauser MA, Schmidt S et al: Complement factor H variant increases the risk of age-related macular degeneration. Science 2005; 308: 419–421.
Edwards AO, Ritter R, Abel KJ et al: Complement factor H polymorphism and age-related macular degeneration. Science 2005; 308: 421–424.
Thakkinstian A, Han P, McEvoy M et al: Systematic review and meta-analysis of the association between complement factor H Y402H polymorphisms and age-related macular degeneration. Hum Mol Genet 2006; 15: 2784–2790.
Yang Z, Camp NJ, Sun H et al: A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration. Science 2006; 314: 992–993.
Yoshida T, Dewan A, Zhang H et al: HTRA1 promoter polymorphism predisposes Japanese to age-related macular degeneration. Mol Vis 2007; 4: 545–548.
Dina C, Meyre D, Samson C et al: Comment on ‘A common genetic variant is associated with adult and childhood obesity’. Science 2007; 315: 187b.
Loos RJF, Barroso I, Rahilly SO, Wareham NJ : Comment on ‘A common genetic variant is associated with adult and childhood obesity’. Science 2007; 315: 187c.
Rosskopf D, Bornhorst A, Rimmbach C et al: Comment on ‘A common genetic variant is associated with adult and childhood obesity’. Science 2007; 315: 187d.
Herbert A, Gerry NP, McQueen MB et al: Response to Comments on ‘A common genetic variant is associated with adult and childhood obesity’. Science 2007; 315: 187e.
Lyon HN, Emilsson V, Hinney A et al: The association of a SNP upstream of INSIG2 with body mass index is reproduced in several but not all cohorts. PLoS Genet 2007; 3: e61.
Cummings JR, Ahmad T, Geremia A et al: Contribution of the novel inflammatory bowel disease gene IL23R to disease susceptibility and phenotype. Inflamm Bowel Dis 2007; 13: 1063–1068.
Van Limbergen JE, Russell RK, Nimmo ER et al: IL23R Arg381Gln is associated with childhood onset inflammatory bowel disease in Scotland. Gut 2007; 56: 1173–1174.
Tremelling M, Cummings F, Fisher SA et al: IL23R variation determines susceptibility but not disease phenotype in inflammatory bowel disease. Gastroenterology 2007; 132: 1657–1664.
Dubinsky MC, Wang D, Picornell Y et al: IL-23 receptor (IL-23R) gene protects against pediatric Crohn's disease. Inflamm Bowel Dis 2007; 13: 511–515.
Hampe J, Franke A, Rosentiel P et al: A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet 2007; 39: 207–211.
Cummings JR, Cooney R, Pathan S et al: Confirmation of the role of ATG16l1 as a Crohn's disease susceptibility gene. Inflamm Bowel Dis 2007; 13: 941–946.
Prescott NJ, Fisher SA, Franke A et al: A nonsynonymous SNP in ATG16L1 predisposes to ileal Crohn's disease and is independent of CARD15 and IBD5. Gastroenterology 2007; 132: 1665–1671.
Cauchi S, El Achhab Y, Choquet H et al: TCF7L2 is reproducibly associated with type 2 diabetes in various ethnic groups: a global meta-analysis. J Mol Med 2007; 85: 777–782.
Cox A, Dunning AM, Garcia-Closas M et al: A common coding variant in CASP8 is associated with breast cancer risk. Nat Genet 2007; 39: 352–358.
Amundadottir LT, Sulem P, Gudmundsson J et al: A common variant associated with prostate cancer in European and African populations. Nat Genet 2006; 38: 652–658.
Haiman CA, Patterson N, Freedman ML et al: Multiple regions within 8q24 independently affect risk for prostate cancer. Nat Genet 2007; 39: 638–644.
Todd JA, Walker NM, Cooper JD et al: Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nat Genet 2007; 39: 857–864.
Lowe CE, Cooper JD, Brusko T et al: Large-scale genetic fine mapping and genotype-phenotype associations implicate polymorphism in the IL2RA region in type 1 diabetes. Nat Genet 2007; 39: 1074–1082.
McPherson R, Pertsemlidis A, Kavaslar N et al: A common allele on chromosome 9 associated with coronary heart disease. Science 2007; 316: 1488–1491.
Helgadottir A, Thorleifsson G, Manolescu A et al: A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science 2007; 316: 1491–1493.
Maraganore DM, de Andrade M, Lesnick TG et al: High-resolution whole-genome association study of Parkinson disease. Am J Hum Genet 2005; 77: 685–693.
Clarimon J, Scholz S, Fung HC et al: Conflicting results regarding the semaphorin gene (SEMA5A) and the risk for Parkinson disease. Am J Hum Genet 2006; 78: 1082–1084.
Goris A, Williams-Gray CH, Foltynie T et al: No evidence for association with Parkinson disease for 13 single-nucleotide polymorphisms identified by whole-genome association screening. Am J Hum Genet 2006; 78: 1088–1090.
Li Y, Rowland C, Schrodi S et al: A case-control association study of the 12 single-nucleotide polymorphisms implicated in Parkinson disease by a recent genome scan. Am J Hum Genet 2006; 78: 1090–1092.
Elbaz A, Nelson LM, Payami H et al: Lack of replication of thirteen single-nucleotide polymorphisms implicated in Parkinson's disease: a large-scale international study. Lancet Neurol 2006; 5: 917–923.
Fung HC, Scholz S, Matarin M et al: Genome-wide genotyping in Parkinson's disease and neurologically normal controls: first stage analysis and public release of data. Lancet Neurol 2006; 5: 911–916.
Matarin M, Brown WM, Scholz S et al: A genome-wide genotyping study in patients with ischaemic stroke: initial analysis and data release. Lancet Neurol 2007; 6: 414–420.
Schymick JC, Scholz SW, Fung HC et al: Genome-wide genotyping in amyotrophic lateral sclerosis and neurologically normal controls: first stage analysis and public release of data. Lancet Neurol 2007; 6: 322–328.
Klein RJ : Power analysis for genome-wide association studies. BMC Genet 2007; 8: 58.
The GAIN Collaborative Research Group: New models of collaboration in genome-wide association studies: the Genetic Association Information Network. Nat Genet 2007; 39: 1045–1051.
Zaykin DV, Zhivotovsky LA : Ranks of genuine associations in whole-genome scans. Genetics 2005; 171: 813–823.
Ragoussis J, Elvidge GP, Kaur K et al: Matrix-assisted laser desorption/ionisation, time-of-flight mass spectrometry in genomics research. PLoS Genet 2006; 2: e100.
Marchini J, Cardon LR, Phillips MS et al: The effects of human population structure on large genetic association studies. Nat Genet 2004; 36: 512–517.
Price AL, Patterson NJ, Plenge RM et al: Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 2006; 38: 904–909.
The ENCODE Project Consortium: Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 2007; 447: 799–816.
The ENCODE Project Consortium: The ENCODE (ENCyclopedia Of DNA Elements) Project. Science 2004; 306: 636–640.
Shriner D, Vaughan LK, Padilla MA, Tiwari HK : Problems with genome-wide association studies. Science 2007; 316: 1840–1842.
Williams SM, Canter JA, Crawford DC et al: Problems with genome-wide association studies. Science 2007; 316: 1840–1842.
Cohen JC, Kiss RS, Pertsemlidis A et al: Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science 2004; 305: 869–872.
Romeo S, Pennacchio LA, Fu Y et al: Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL. Nat Genet 2007; 39: 513–516.
Stefansson H, Rye DB, Hicks A et al: A genetic risk factor for periodic limb movements in sleep. N Engl J Med 2007; 357: 639–647.
Winkelmann J, Schormair B, Lichtner P et al: Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions. Nat Genet 2007; 39: 1000–1006.
Samani NJ, Erdmann J, Hall AS et al: Genome wide association analysis of coronary artery disease. N Engl J Med 2007; 357: 443–453.
The International Multiple Sclerosis Genetics Consortium: Risk alleles for multiple sclerosis identified by a genome wide study. N Engl J Med 2007; 357: 851–862.
Buch S, Schafmayer C, Volzke H et al: A genome-wide association scan identifies the hepatic cholesterol transporter ABCG8 as a susceptibility factor for human gallstone disease. Nat Genet 2007; 39: 995–999.
Thorleifsson G, Magnusson KP, Sulem P et al: Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma. Science 2007; 317: 1397–1400.
Tomlinson I, Webb E, Carvajal-Carmona L et al: A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21. Nat Genet 2007; 39: 984–988.
Zanke BW, Greenwood CM, Rangrej J et al: Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24. Nat Genet 2007; 39: 989–994.
Fellay J, Shianna KV, Ge D et al: A whole-genome association study of major determinants for host control of HIV-1. Science 2007; 317: 944–947.
Hakonarson H, Grant SF, Bradfield JP et al: A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene. Nature 2007; 448: 591–594.
Moffatt MF, Kabesch M, Liang L et al: Genetic variants regulating ORMDL3 expression contributes to the risk of childhood asthma. Nature 2007; 448: 470–473.
Gudbjartsson DF, Arnar DO, Helgadottir A et al: Variants conferring risk of atrial fibrillation on chromosome 4q25. Nature 2007; 448: 353–357.
van Es MA, Van Vught PW, Blauw HM et al: ITPR2 as a susceptibility gene in sporadic amyotrophic lateral sclerosis: a genome-wide association study. Lancet Neurol 2007; 6: 869–877.
Dunckley T, Huentelman MJ, Craig DW et al: Whole-genome analysis of sporadic amyotrophic lateral sclerosis. N Engl J Med 2007; 357: 775–788.
Plenge RM, Seielstad M, Padyukov L et al: TRAF1-C5 as a risk locus for rheumatoid arthritis – a genome wide study. N Engl J Med 2007; 357: 1199–1209.
Plenge RM, Cotsapas C, Davies L et al: Two independent alleles at 6q23 associated with risk of rheumatoid arthritis. Nat Genet 2007; 39: 1477–1482.
Acknowledgements
The authors declare no conflicts of interest. We are grateful to Dr Sonia Davila (Genome Institute of Singapore) for her valuable comments and kind assistance in revising this paper. We are thankful to Kaavya Narasimhalu (Center for Molecular Epidemiology, National University of Singapore) for critical proofreading of this review paper.
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Seng, K., Seng, C. The success of the genome-wide association approach: a brief story of a long struggle. Eur J Hum Genet 16, 554–564 (2008). https://doi.org/10.1038/ejhg.2008.12
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DOI: https://doi.org/10.1038/ejhg.2008.12
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