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Genome-wide association studies: a primer

Published online by Cambridge University Press:  09 November 2009

A. Corvin ,
N. Craddock  and
P. F. Sullivan
A. Corvin
Affiliation:
Department of Psychiatry, Trinity College Dublin, Dublin, Ireland
N. Craddock
Affiliation:
Department of Psychological Medicine, School of Medicine, Cardiff, UK
P. F. Sullivan*
Affiliation:
Department of Genetics, University of North Carolina at Chapel Hill, NC, USA
*
*Address for correspondence: P. F. Sullivan, M.D., FRANZCP, Department of Genetics, CB#7264, 4109D Neurosciences Research Building, University of North Carolina, Chapel Hill, NC27599-7264, USA. (Email: [email protected])
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Abstract

There have been nearly 400 genome-wide association studies (GWAS) published since 2005. The GWAS approach has been exceptionally successful in identifying common genetic variants that predispose to a variety of complex human diseases and biochemical and anthropometric traits. Although this approach is relatively new, there are many excellent reviews of different aspects of the GWAS method. Here, we provide a primer, an annotated overview of the GWAS method with particular reference to psychiatric genetics. We dissect the GWAS methodology into its components and provide a brief description with citations and links to reviews that cover the topic in detail.

Keywords

Genome-wide association studypsychiatric geneticsreview
Type
Review Article
Information
Psychological Medicine , Volume 40 , Issue 7 , July 2010 , pp. 1063 - 1077
Copyright
Copyright © Cambridge University Press 2009

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References

Allen, N, Bagade, S, McQueen, M, Ioannidis, J, Kavvoura, F, Khoury, M, Tanzi, R, Bertram, L (2008). Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. Nature Genetics 40, 827–834.CrossRefGoogle ScholarPubMed
Arranz, MJ, Kapur, S (2008). Pharmacogenetics in psychiatry: are we ready for widespread clinical use? Schizophrenia Bulletin 34, 1130–1144.Google Scholar
Attia, J, Ioannidis, JP, Thakkinstian, A, McEvoy, M, Scott, RJ, Minelli, C, Thompson, J, Infante-Rivard, C, Guyatt, G (2009 a). How to use an article about genetic association: A: Background concepts. Journal of the American Medical Association 301, 74–81.CrossRefGoogle Scholar
Attia, J, Ioannidis, JP, Thakkinstian, A, McEvoy, M, Scott, RJ, Minelli, C, Thompson, J, Infante-Rivard, C, Guyatt, G (2009 b). How to use an article about genetic association: B: Are the results of the study valid? Journal of the American Medical Association 301, 191–197.Google Scholar
Barrett, JC, Clayton, DG, Concannon, P, Akolkar, B, Cooper, JD, Erlich, HA, Julier, C, Morahan, G, Nerup, J, Nierras, C, Plagnol, V, Pociot, F, Schuilenburg, H, Smyth, DJ, Stevens, H, Todd, JA, Walker, NM, Rich, SS (2009). Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nature Genetics 41, 703–707.Google Scholar
Barrett, JC, Hansoul, S, Nicolae, DL, Cho, JH, Duerr, RH, Rioux, JD, Brant, SR, Silverberg, MS, Taylor, KD, Barmada, MM, Bitton, A, Dassopoulos, T, Datta, LW, Green, T, Griffiths, AM, Kistner, EO, Murtha, MT, Regueiro, MD, Rotter, JI, Schumm, LP, Steinhart, AH, Targan, SR, Xavier, RJ, Libioulle, C, Sandor, C, Lathrop, M, Belaiche, J, Dewit, O, Gut, I, Heath, S, Laukens, D, Mni, M, Rutgeerts, P, Van Gossum, A, Zelenika, D, Franchimont, D, Hugot, JP, de Vos, M, Vermeire, S, Louis, E, Cardon, LR, Anderson, CA, Drummond, H, Nimmo, E, Ahmad, T, Prescott, NJ, Onnie, CM, Fisher, SA, Marchini, J, Ghori, J, Bumpstead, S, Gwilliam, R, Tremelling, M, Deloukas, P, Mansfield, J, Jewell, D, Satsangi, J, Mathew, CG, Parkes, M, Georges, M, Daly, MJ (2008). Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nature Genetics 40, 955–962.CrossRefGoogle ScholarPubMed
Chanock, SJ, Manolio, T, Boehnke, M, Boerwinkle, E, Hunter, DJ, Thomas, G, Hirschhorn, JN, Abecasis, G, Altshuler, D, Bailey-Wilson, JE, Brooks, LD, Cardon, LR, Daly, M, Donnelly, P, Fraumeni, JF Jr., Freimer, NB, Gerhard, DS, Gunter, C, Guttmacher, AE, Guyer, MS, Harris, EL, Hoh, J, Hoover, R, Kong, CA, Merikangas, KR, Morton, CC, Palmer, LJ, Phimister, EG, Rice, JP, Roberts, J, Rotimi, C, Tucker, MA, Vogan, KJ, Wacholder, S, Wijsman, EM, Winn, DM, Collins, FS (2007). Replicating genotype–phenotype associations. Nature 447, 655–660.Google Scholar
Cook, EH Jr., Scherer, SW (2008). Copy-number variations associated with neuropsychiatric conditions. Nature 455, 919–923.CrossRefGoogle ScholarPubMed
Craddock, N, O'Donovan, MC, Owen, MJ (2007). Phenotypic and genetic complexity of psychosis. British Journal of Psychiatry 190, 200–203.Google Scholar
Cross-Disorder Phenotype Group of the Psychiatric GWAS Consortium (2009). Dissecting the phenotype in genome-wide association studies of psychiatric illness. British Journal of Psychiatry 195, 97–99.CrossRefGoogle Scholar
Crow, TJ (2008). Schizophrenia: the polygene emperors have no clothes. Psychological Medicine 38, 1681–1685.CrossRefGoogle ScholarPubMed
de Bakker, PI, Ferreira, MA, Jia, X, Neale, BM, Raychaudhuri, S, Voight, BF (2008). Practical aspects of imputation-driven meta-analysis of genome-wide association studies. Human Molecular Genetics 17, R122–R128.Google Scholar
Esslinger, C, Walter, H, Kirsch, P, Erk, S, Schnell, K, Arnold, C, Haddad, L, Mier, D, Opitz von Boberfeld, C, Raab, K, Witt, SH, Rietschel, M, Cichon, S, Meyer-Lindenberg, A (2009). Neural mechanisms of a genome-wide supported psychosis variant. Science 324, 605.CrossRefGoogle ScholarPubMed
Ferreira, M, O'Donovan, M, Meng, Y, Jones, I, Ruderfer, D, Jones, L, Fan, J, Kirov, G, Perlis, R, Green, E, Smoller, J, Grozeva, D, Stone, J, Nikolov, I, Chambert, K, Hamshere, M, Nimgaonkar, V, Moskvina, V, Thase, M, Caesar, S, Sachs, G, Franklin, J, Gordon-Smith, K, Ardlie, K, Gabriel, S, Fraser, C, Blumenstiel, B, Defelice, M, Breen, G, Gill, M, Morris, D, Elkin, A, Muir, W, McGhee, K, Williamson, R, MacIntyre, D, McLean, A, St Clair, D, VanBeck, M, Pereira, A, Kandaswamy, R, McQuillin, A, Collier, D, Bass, N, Young, A, Lawrence, J, Ferrier, I, Anjorin, A, Farmer, A, Curtis, D, Scolnick, E, McGuffin, P, Daly, M, Corvin, A, Holmans, P, Blackwood, D, Gurling, H, Owen, M, Purcell, S, Sklar, P, Craddock, N (2008). Collaborative genome-wide association analysis of 10,596 individuals supports a role for Ankyrin-G (ANK3) and the alpha-1C subunit of the L-type voltage-gated calcium channel (CACNA1C) in bipolar disorder. Nature Genetics 40, 1056–1058.CrossRefGoogle Scholar
Goldstein, DB (2009). Common genetic variation and human traits. New England Journal of Medicine 360, 1696–1698.CrossRefGoogle ScholarPubMed
Hardy, J, Singleton, A (2009). Genomewide association studies and human disease. New England Journal of Medicine 360, 1759–1768.Google Scholar
Holmans, P, Green, EK, Pahwa, JS, Ferreira, MA, Purcell, SM, Sklar, P, Owen, MJ, O'Donovan, MC, Craddock, N (2009). Gene ontology analysis of GWA study data sets provides insights into the biology of bipolar disorder. American Journal of Human Genetics 85, 13–24.Google Scholar
Hong, MG, Pawitan, Y, Magnusson, PK, Prince, JA (2009). Strategies and issues in the detection of pathway enrichment in genome-wide association studies. Human Genetics 126, 289–301.Google Scholar
International Schizophrenia Consortium (2009). Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460, 748–752.CrossRefGoogle Scholar
Ioannidis, JP, Thomas, G, Daly, MJ (2009). Validating, augmenting and refining genome-wide association signals. Nature Reviews Genetics 10, 318–329.CrossRefGoogle ScholarPubMed
Kaye, J (2008). The regulation of direct-to-consumer genetic tests. Human Molecular Genetics 17, R180–R183.Google Scholar
Kendler, KS (2006). Reflections on the relationship between psychiatric genetics and psychiatric nosology. American Journal of Psychiatry 163, 1138–1146.Google Scholar
Klein, RJ, Zeiss, C, Chew, EY, Tsai, JY, Sackler, RS, Haynes, C, Henning, AK, Sangiovanni, JP, Mane, SM, Mayne, ST, Bracken, MB, Ferris, FL, Ott, J, Barnstable, C, Hoh, J (2005). Complement factor H polymorphism in age-related macular degeneration. Science 308, 385–389.Google Scholar
Konneker, T, Barnes, T, Furberg, H, Losh, M, Bulik, CM, Sullivan, PF (2008). A searchable database of genetic evidence for psychiatric disorders. American Journal of Medical Genetics (Neuropsychiatric Genetics) 147, 671–675.CrossRefGoogle Scholar
Kraft, P, Hunter, DJ (2009). Genetic risk prediction – are we there yet? New England Journal of Medicine 360, 1701–1703.CrossRefGoogle ScholarPubMed
Lichtenstein, P, Yip, B, Bjork, C, Pawitan, Y, Cannon, TD, Sullivan, PF, Hultman, CM (2009). Common genetic influences for schizophrenia and bipolar disorder: a population-based study of 2 million nuclear families. Lancet 373, 234–239.CrossRefGoogle Scholar
Lunshof, JE, Chadwick, R, Vorhaus, DB, Church, GM (2008). From genetic privacy to open consent. Nature Reviews Genetics 9, 406–411.CrossRefGoogle ScholarPubMed
McCarthy, MI, Abecasis, GR, Cardon, LR, Goldstein, DB, Little, J, Ioannidis, JP, Hirschhorn, JN (2008). Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nature Reviews Genetics 9, 356–369.Google Scholar
Mitchell, K, Porteus, D (2009). GWAS for psychiatric disease: is the framework built on a solid foundation? Molecular Psychiatry 14, 740–741.CrossRefGoogle ScholarPubMed
Neale, BM, Purcell, S (2008). The positives, protocols, and perils of genome-wide association. American Journal of Medical Genetics (Neuropsychiatric Genetics) 147B, 1288–1294.CrossRefGoogle ScholarPubMed
Nussbaum, R, McInnes, R, Willard, HF (2007). Thompson & Thompson Genetics in Medicine. Elsevier Science: New York.Google Scholar
O'Donovan, M, Craddock, N, Norton, N, Williams, H, Peirce, T, Moskvina, V, Nikolov, I, Hamshere, M, Carroll, L, Georgieva, L, Dwyer, S, Holmans, P, Marchini, J, Spencer, C, Howie, B, Leung, H-T, Hartmann, A, Möller, H-J, Morris, D, Shi, Y, Feng, G, Hoffmann, P, Propping, P, Vasilescu, C, Maier, W, Rieschel, M, Zammit, S, Schumacher, J, Quinn, E, Schulze, T, Williams, N, Giegling, I, Iwata, N, Ikeda, M, Darvasi, A, Shifman, S, He, L, Duan, J, Sanders, A, Levinson, D, Gejman, P, Cichon, S, Nöthen, M, Gill, M, Corvin, A, Rujescu, D, Kirov, G, Owen, M (2008). Identification of novel schizophrenia loci by genome-wide association and follow-up. Nature Genetics 40, 1053–1055.Google Scholar
Pe'er, I, Yelensky, R, Altshuler, D, Daly, MJ (2008). Estimation of the multiple testing burden for genomewide association studies of nearly all common variants. Genetic Epidemiology 32, 381–385.Google Scholar
Psychiatric GWAS Consortium (2009 a). A framework for interpreting genomewide association studies of psychiatric disorders. Molecular Psychiatry 14, 10–17.CrossRefGoogle Scholar
Psychiatric GWAS Consortium (2009 b). Genome-wide association studies: history, rationale, and prospects for psychiatric disorders. American Journal of Psychiatry 166, 540–546.CrossRefGoogle Scholar
Rothman, KJ (1986). Modern Epidemiology. Little, Brown, and Company: Boston.Google Scholar
Rothstein, MA (2005). Science and society: applications of behavioural genetics: outpacing the science? Nature Reviews Genetics 6, 793–798.CrossRefGoogle ScholarPubMed
Saxena, R, Voight, BF, Lyssenko, V, Burtt, NP, de Bakker, PI, Chen, H, Roix, JJ, Kathiresan, S, Hirschhorn, JN, Daly, MJ, Hughes, TE, Groop, L, Altshuler, D, Almgren, P, Florez, JC, Meyer, J, Ardlie, K, Bengtsson, K, Isomaa, B, Lettre, G, Lindblad, U, Lyon, HN, Melander, O, Newton-Cheh, C, Nilsson, P, Orho-Melander, M, Rastam, L, Speliotes, EK, Taskinen, MR, Tuomi, T, Guiducci, C, Berglund, A, Carlson, J, Gianniny, L, Hackett, R, Hall, L, Holmkvist, J, Laurila, E, Sjogren, M, Sterner, M, Surti, A, Svensson, M, Tewhey, R, Blumenstiel, B, Parkin, M, Defelice, M, Barry, R, Brodeur, W, Camarata, J, Chia, N, Fava, M, Gibbons, J, Handsaker, B, Healy, C, Nguyen, K, Gates, C, Sougnez, C, Gage, D, Nizzari, M, Gabriel, SB, Chirn, GW, Ma, Q, Parikh, H, Richardson, D, Ricke, D, Purcell, S (2007). Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316, 1331–1336.Google Scholar
Scherer, SW, Lee, C, Birney, E, Altshuler, DM, Eichler, EE, Carter, NP, Hurles, ME, Feuk, L (2007). Challenges and standards in integrating surveys of structural variation. Nature Genetics 39, S7–S15.Google Scholar
Schlesselman, JJ (1982). Case-control Studies: Design, Conduct, Analysis. Oxford University Press: New York.Google Scholar
Schulze, TG, McMahon, FJ (2004). Defining the phenotype in human genetic studies: forward genetics and reverse phenotyping. Human Heredity 58, 131–138.Google Scholar
Scott, LJ, Mohlke, KL, Bonnycastle, LL, Willer, CJ, Li, Y, Duren, WL, Erdos, MR, Stringham, HM, Chines, PS, Jackson, AU, Prokunina-Olsson, L, Ding, CJ, Swift, AJ, Narisu, N, Hu, T, Pruim, R, Xiao, R, Li, XY, Conneely, KN, Riebow, NL, Sprau, AG, Tong, M, White, PP, Hetrick, KN, Barnhart, MW, Bark, CW, Goldstein, JL, Watkins, L, Xiang, F, Saramies, J, Buchanan, TA, Watanabe, RM, Valle, TT, Kinnunen, L, Abecasis, GR, Pugh, EW, Doheny, KF, Bergman, RN, Tuomilehto, J, Collins, FS, Boehnke, M (2007). A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316, 1341–1345.Google Scholar
Shi, J, Levinson, DF, Duan, J, Sanders, AR, Zheng, Y, Pe'er, I, Dudbridge, F, Holmans, PA, Whittemore, AS, Mowry, BJ, Olincy, A, Amin, F, Cloninger, CR, Silverman, JM, Buccola, NG, Byerley, WF, Black, DW, Crowe, RR, Oksenberg, JR, Mirel, DB, Kendler, KS, Freedman, R, Gejman, PV (2009). Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature 460, 753–757.CrossRefGoogle ScholarPubMed
Stefansson, H, Ophoff, RA, Steinberg, S, Andreassen, OA, Cichon, S, Rujescu, D, Werge, T, Pietilainen, OP, Mors, O, Mortensen, PB, Sigurdsson, E, Gustafsson, O, Nyegaard, M, Tuulio-Henriksson, A, Ingason, A, Hansen, T, Suvisaari, J, Lonnqvist, J, Paunio, T, Borglum, AD, Hartmann, A, Fink-Jensen, A, Nordentoft, M, Hougaard, D, Norgaard-Pedersen, B, Bottcher, Y, Olesen, J, Breuer, R, Moller, HJ, Giegling, I, Rasmussen, HB, Timm, S, Mattheisen, M, Bitter, I, Rethelyi, JM, Magnusdottir, BB, Sigmundsson, T, Olason, P, Masson, G, Gulcher, JR, Haraldsson, M, Fossdal, R, Thorgeirsson, TE, Thorsteinsdottir, U, Ruggeri, M, Tosato, S, Franke, B, Strengman, E, Kiemeney, LA, Genetic Risk and Outcome in Psychosis (GROUP); Melle, I, Djurovic, S, Abramova, L, Kaleda, V, Sanjuan, J, de Frutos, R, Bramon, E, Vassos, E, Fraser, G, Ettinger, U, Picchioni, M, Walker, N, Toulopoulou, T, Need, AC, Ge, D, Lim Yoon, J, Shianna, KV, Freimer, NB, Cantor, RM, Murray, R, Kong, A, Golimbet, V, Carracedo, A, Arango, C, Costas, J, Jonsson, EG, Terenius, L, Agartz, I, Petursson, H, Nothen, MM, Rietschel, M, Matthews, PM, Muglia, P, Peltonen, L, St Clair, D, Goldstein, DB, Stefansson, K, Collier, DA, Kahn, RS, Linszen, DH, van Os, J, Wiersma, D, Bruggeman, R, Cahn, W, de Haan, L, Krabbendam, L, Myin-Germeys, I (2009). Common variants conferring risk of schizophrenia. Nature 460, 744–747.CrossRefGoogle ScholarPubMed
Strachen, T, Read, AP (2003). Human Molecular Genetics. John Wiley & Sons: New York.Google Scholar
Sullivan, PF, Gejman, PV (in press). Response to Mitchell & Porteus, Molecular Psychiatry (2009) 14, 740–741. Molecular Psychiatry.Google Scholar
Wang, K, Zhang, H, Ma, D, Bucan, M, Glessner, JT, Abrahams, BS, Salyakina, D, Imielinski, M, Bradfield, JP, Sleiman, PM, Kim, CE, Hou, C, Frackelton, E, Chiavacci, R, Takahashi, N, Sakurai, T, Rappaport, E, Lajonchere, CM, Munson, J, Estes, A, Korvatska, O, Piven, J, Sonnenblick, LI, Alvarez Retuerto, AI, Herman, EI, Dong, H, Hutman, T, Sigman, M, Ozonoff, S, Klin, A, Owley, T, Sweeney, JA, Brune, CW, Cantor, RM, Bernier, R, Gilbert, JR, Cuccaro, ML, McMahon, WM, Miller, J, State, MW, Wassink, TH, Coon, H, Levy, SE, Schultz, RT, Nurnberger, JI, Haines, JL, Sutcliffe, JS, Cook, EH, Minshew, NJ, Buxbaum, JD, Dawson, G, Grant, SF, Geschwind, DH, Pericak-Vance, MA, Schellenberg, GD, Hakonarson, H (2009). Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature 459, 528–533.CrossRefGoogle ScholarPubMed
WTCCC (2007). Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678.CrossRefGoogle Scholar
Xu, Z, Taylor, JA (2009). SNPinfo: integrating GWAS and candidate gene information into functional SNP selection for genetic association studies. Nucleic Acids Research 37, W600–W605.CrossRefGoogle ScholarPubMed
Zeggini, E, Scott, LJ, Saxena, R, Voight, BF, Marchini, JL, Hu, T, de Bakker, PI, Abecasis, GR, Almgren, P, Andersen, G, Ardlie, K, Bostrom, KB, Bergman, RN, Bonnycastle, LL, Borch-Johnsen, K, Burtt, NP, Chen, H, Chines, PS, Daly, MJ, Deodhar, P, Ding, CJ, Doney, AS, Duren, WL, Elliott, KS, Erdos, MR, Frayling, TM, Freathy, RM, Gianniny, L, Grallert, H, Grarup, N, Groves, CJ, Guiducci, C, Hansen, T, Herder, C, Hitman, GA, Hughes, TE, Isomaa, B, Jackson, AU, Jorgensen, T, Kong, A, Kubalanza, K, Kuruvilla, FG, Kuusisto, J, Langenberg, C, Lango, H, Lauritzen, T, Li, Y, Lindgren, CM, Lyssenko, V, Marvelle, AF, Meisinger, C, Midthjell, K, Mohlke, KL, Morken, MA, Morris, AD, Narisu, N, Nilsson, P, Owen, KR, Palmer, CN, Payne, F, Perry, JR, Pettersen, E, Platou, C, Prokopenko, I, Qi, L, Qin, L, Rayner, NW, Rees, M, Roix, JJ, Sandbaek, A, Shields, B, Sjogren, M, Steinthorsdottir, V, Stringham, HM, Swift, AJ, Thorleifsson, G, Thorsteinsdottir, U, Timpson, NJ, Tuomi, T, Tuomilehto, J, Walker, M, Watanabe, RM, Weedon, MN, Willer, CJ, Illig, T, Hveem, K, Hu, FB, Laakso, M, Stefansson, K, Pedersen, O, Wareham, NJ, Barroso, I, Hattersley, AT, Collins, FS, Groop, L, McCarthy, MI, Boehnke, M, Altshuler, D (2008). Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nature Genetics 40, 638–645.Google Scholar