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Hypothesis-driven candidate genes for schizophrenia compared to genome-wide association results

Published online by Cambridge University Press:  19 August 2011

A. L. Collins ,
Y. Kim ,
P. Sklar ,
M. C. O'Donovan  and
P. F. Sullivan
A. L. Collins*
Affiliation:
Department of Genetics, University of North Carolina at Chapel Hill, NC, USA
Y. Kim
Affiliation:
Department of Genetics, University of North Carolina at Chapel Hill, NC, USA
P. Sklar
Affiliation:
Department of Psychiatry, Mt Sinai School of Medicine, New York, NY, USA
M. C. O'Donovan
Affiliation:
MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, UK
P. F. Sullivan*
Affiliation:
Department of Genetics, University of North Carolina at Chapel Hill, NC, USA
*
(Email: [email protected]) [A.L.C.]
*Address for correspondence: P. F. Sullivan, M.D., FRANZCP, Department of Genetics, CB#7264, 5097 Genomic Medicine, University of North Carolina, Chapel Hill, NC 27599-7264, USA. (Email: [email protected]) [P.F.S.]
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Abstract

Background

Candidate gene studies have been a key approach to the genetics of schizophrenia (SCZ). However, the results of these studies are confusing and no genes have been unequivocally implicated. The hypothesis-driven candidate gene literature can be appraised by comparison with the results of genome-wide association studies (GWAS).

Method

We describe the characteristics of hypothesis-driven candidate gene studies from the SZGene database, and use pathway analysis to compare hypothesis-driven candidate genes with GWAS results from the International Schizophrenia Consortium (ISC).

Results

SZGene contained 732 autosomal genes evaluated in 1374 studies. These genes had poor statistical power to detect genetic effects typical for human diseases, assessed only 3.7% of genes in the genome, and had low marker densities per gene. Most genes were assessed once or twice (76.9%), providing minimal ability to evaluate consensus across studies. The ISC studies had 89% power to detect a genetic effect typical for common human diseases and assessed 79% of known autosomal common genetic variation. Pathway analyses did not reveal enrichment of smaller ISC p values in hypothesis-driven candidate genes, nor did a comprehensive evaluation of meta-hypotheses driving candidate gene selection (SCZ as a disease of the synapse or neurodevelopment). The most studied hypothesis-driven candidate genes (COMT, DRD3, DRD2, HTR2A, NRG1, BDNF, DTNBP1 and SLC6A4) had no notable ISC results.

Conclusions

We did not find support for the idea that the hypothesis-driven candidate genes studied in the literature are enriched for the common genetic variation involved in the etiology of SCZ. Larger samples are required to evaluate this conclusion definitively.

Keywords

Candidate gene associationcomparative studygeneticsgenome-wide associationneurodevelopmentalschizophreniasynapse
Type
Original Articles
Information
Psychological Medicine , Volume 42 , Issue 3 , March 2012 , pp. 607 - 616
Copyright
Copyright © Cambridge University Press 2011

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References

Allen, NC, Bagade, S, McQueen, MB, Ioannidis, JP, Kavvoura, FK, Khoury, MJ, Tanzi, RE, 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
Athanasiu, L, Mattingsdal, M, Kahler, AK, Brown, A, Gustafsson, O, Agartz, I, Giegling, I, Muglia, P, Cichon, S, Rietschel, M, Pietilainen, OP, Peltonen, L, Bramon, E, Collier, D, Clair, DS, Sigurdsson, E, Petursson, H, Rujescu, D, Melle, I, Steen, VM, Djurovic, S, Andreassen, OA (2010). Gene variants associated with schizophrenia in a Norwegian genome-wide study are replicated in a large European cohort. Journal of Psychiatric Research 44, 748–753.CrossRefGoogle Scholar
Beaudet, AL, Belmont, JW (2008). Array-based DNA diagnostics: let the revolution begin. Annual Review of Medicine 59, 113–129.CrossRefGoogle ScholarPubMed
Bowen, T, Guy, CA, Cardno, AG, Vincent, JB, Kennedy, JL, Jones, LA, Gray, M, Sanders, RD, McCarthy, G, Murphy, KC, Owen, MJ, O'Donovan, MC (2000). Repeat sizes at CAG/CTG loci CTG18.1, ERDA1 and TGC13-7a in schizophrenia. Psychiatric Genetics 10, 33–37.CrossRefGoogle ScholarPubMed
Browning, BL, Browning, SR (2009). A unified approach to genotype imputation and haplotype-phase inference for large data sets of trios and unrelated individuals. American Journal of Human Genetics 84, 210–223.CrossRefGoogle ScholarPubMed
Browning, SR, Browning, BL (2007). Rapid and accurate haplotype phasing and missing-data inference for whole-genome association studies by use of localized haplotype clustering. American Journal of Human Genetics 81, 1084–1097.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, Jr. JF, 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 ScholarPubMed
Cichon, S, Craddock, N, Daly, M, Faraone, SV, Gejman, PV, Kelsoe, J, Lehner, T, Levinson, DF, Moran, A, Sklar, P, Sullivan, PF (2009). Genomewide association studies: history, rationale, and prospects for psychiatric disorders. American Journal of Psychiatry 166, 540–556.Google ScholarPubMed
Dennis, G Jr., Sherman, BT, Hosack, DA, Yang, J, Gao, W, Lane, HC, Lempicki, RA (2003). DAVID: Database for Annotation, Visualization, and Integrated Discovery. Genome Biology 4, P3.CrossRefGoogle ScholarPubMed
Gauderman, W, Morrison, J (2006). QUANTO 1.1: a computer program for power and sample size calculations for genetic-epidemiology studies (http://hydra.usc.edu/gxe).Google Scholar
Gauderman, WJ (2002). Sample size requirements for matched case-control studies of gene-environment interaction. Statistics in Medicine 21, 35–50.CrossRefGoogle ScholarPubMed
Harris, MA, Clark, J, Ireland, A, Lomax, J, Ashburner, M, Foulger, R, Eilbeck, K, Lewis, S, Marshall, B, Mungall, C, Richter, J, Rubin, GM, Blake, JA, Bult, C, Dolan, M, Drabkin, H, Eppig, JT, Hill, DP, Ni, L, Ringwald, M, Balakrishnan, R, Cherry, JM, Christie, KR, Costanzo, MC, Dwight, SS, Engel, S, Fisk, DG, Hirschman, JE, Hong, EL, Nash, RS, Sethuraman, A, Theesfeld, CL, Botstein, D, Dolinski, K, Feierbach, B, Berardini, T, Mundodi, S, Rhee, SY, Apweiler, R, Barrell, D, Camon, E, Dimmer, E, Lee, V, Chisholm, R, Gaudet, P, Kibbe, W, Kishore, R, Schwarz, EM, Sternberg, P, Gwinn, M, Hannick, L, Wortman, J, Berriman, M, Wood, V, de la Cruz, N, Tonellato, P, Jaiswal, P, Seigfried, T, White, R; Gene Ontology Consortium (2004). The Gene Ontology (GO) database and informatics resource. Nucleic Acids Research 32, D258–D261.Google ScholarPubMed
Hindorff, LA, Sethupathy, P, Junkins, HA, Ramos, EM, Mehta, JP, Collins, FS, Manolio, TA (2009). Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proceedings of the National Academy of Sciences USA 106, 9362–9367.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Huang, DW, Sherman, BT, Lempicki, RA (2009). Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nature Protocols 4, 44–57.CrossRefGoogle ScholarPubMed
International HapMap Consortium (2005). A haplotype map of the human genome. Nature 437, 1299–1320.CrossRefGoogle Scholar
International Schizophrenia Consortium (2008). Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 455, 237–241.CrossRefGoogle Scholar
Ioannidis, JP, Ntzani, EE, Trikalinos, TA, Contopoulos-Ioannidis, DG (2001). Replication validity of genetic association studies. Nature Genetics 29, 306–309.CrossRefGoogle ScholarPubMed
Kirov, G, Zaharieva, I, Georgieva, L, Moskvina, V, Nikolov, I, Cichon, S, Hillmer, A, Toncheva, D, Owen, MJ, O'Donovan, MC (2009). A genome-wide association study in 574 schizophrenia trios using DNA pooling. Molecular Psychiatry 14, 796–803.CrossRefGoogle ScholarPubMed
Konneker, TI, Crowley, JJ, Quackenbush, CR, Keefe, RS, Perkins, DO, Stroup, TS, Lieberman, JA, van den Oord, E, Sullivan, PF (2010). No association of the serotonin transporter polymorphisms 5-HTTLPR and rs2553 with schizophrenia or neurocognition. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 153B, 1115–1117.CrossRefGoogle ScholarPubMed
Korn, JM, Kuruvilla, FG, McCarroll, SA, Wysoker, A, Nemesh, J, Cawley, S, Hubbell, E, Veitch, J, Collins, PJ, Darvishi, K, Lee, C, Nizzari, MM, Gabriel, SB, Purcell, S, Daly, MJ, Altshuler, D (2008). Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms and rare CNVs. Nature Genetics 40, 1253–1260.CrossRefGoogle ScholarPubMed
Lee, PH, O'Dushlaine, C, Thomas, B, Holmans, P, Purcell, S (2011). InRich: Interval-based enrichment analysis for genome-wide association studies (http://pngu.mgh.harvard.edu/~purcell/inrich/).Google Scholar
Lencz, T, Morgan, TV, Athanasiou, M, Dain, B, Reed, CR, Kane, JM, Kucherlapati, R, Malhotra, AK (2007). Converging evidence for a pseudoautosomal cytokine receptor gene locus in schizophrenia. Molecular Psychiatry 12, 572–580.CrossRefGoogle ScholarPubMed
McInnis, MG, Swift-Scanlanl, T, Mahoney, AT, Vincent, J, Verheyen, G, Lan, TH, Oruc, L, Riess, O, Van Broeckhoven, C, Chen, H, Kennedy, JL, MacKinnon, DF, Margolis, RL, Simpson, SG, McMahon, FJ, Gershon, E, Nurnberger, J, Reich, T, DePaulo, JR, Ross, CA (2000). Allelic distribution of CTG18.1 in Caucasian populations: association studies in bipolar disorder, schizophrenia, and ataxia. Molecular Psychiatry 5, 439–442.CrossRefGoogle ScholarPubMed
Need, AC, Ge, D, Weale, ME, Maia, J, Feng, S, Heinzen, EL, Shianna, KV, Yoon, W, Kasperaviciute, D, Gennarelli, M, Strittmatter, WJ, Bonvicini, C, Rossi, G, Jayathilake, K, Cola, PA, McEvoy, JP, Keefe, RS, Fisher, EM, St Jean, PL, Giegling, I, Hartmann, AM, Moller, HJ, Ruppert, A, Fraser, G, Crombie, C, Middleton, LT, St Clair, D, Roses, AD, Muglia, P, Francks, C, Rujescu, D, Meltzer, HY, Goldstein, DB (2009). A genome-wide investigation of SNPs and CNVs in schizophrenia. PLoS Genetics 5, e1000373.CrossRefGoogle ScholarPubMed
O'Donovan, MC, Craddock, N, Norton, N, Williams, H, Peirce, T, Moskvina, V, Nikolov, I, Hamshere, M, Carroll, L, Georgieva, L, Dwyer, S, Holmans, P, Marchini, JL, Spencer, CC, Howie, B, Leung, HT, Hartmann, AM, Moller, HJ, Morris, DW, Shi, Y, Feng, G, Hoffmann, P, Propping, P, Vasilescu, C, Maier, W, Rietschel, M, Zammit, S, Schumacher, J, Quinn, EM, Schulze, TG, Williams, NM, Giegling, I, Iwata, N, Ikeda, M, Darvasi, A, Shifman, S, He, L, Duan, J, Sanders, AR, Levinson, DF, Gejman, PV, Cichon, S, Nothen, MM, Gill, M, Corvin, A, Rujescu, D, Kirov, G, Owen, MJ, Buccola, NG, Mowry, BJ, Freedman, R, Amin, F, Black, DW, Silverman, JM, Byerley, WF, Cloninger, CR (2008). Identification of loci associated with schizophrenia by genome-wide association and follow-up. Nature Genetics 40, 1053–1055.CrossRefGoogle ScholarPubMed
Pearson, TA, Manolio, TA (2008). How to interpret a genome-wide association study. Journal of the American Medical Association 299, 1335–1344.CrossRefGoogle ScholarPubMed
Pruitt, KD, Tatusova, T, Maglott, DR (2005). NCBI Reference Sequence (RefSeq): a curated non-redundant sequence database of genomes, transcripts and proteins. Nucleic Acids Research 33, D501–D504.CrossRefGoogle ScholarPubMed
Purcell, SM, Wray, NR, Stone, JL, Visscher, PM, O'Donovan, MC, Sullivan, PF, Sklar, P (2009). Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460, 748–752.Google ScholarPubMed
SAS Institute Inc (2004). SAS/STAT® Software: Version 9. SAS Institute, Inc.: Cary, NC.Google Scholar
SAS Institute Inc (2005). JMP User's Guide (Version 6). SAS Institute, Inc.: Cary, NC.Google Scholar
Sherman, BT, Huang, DW, Tan, Q, Guo, Y, Bour, S, Liu, D, Stephens, R, Baseler, MW, Lane, HC, Lempicki, RA (2007). DAVID Knowledgebase: a gene-centered database integrating heterogeneous gene annotation resources to facilitate high-throughput gene functional analysis. BMC Bioinformatics 8, 426.CrossRefGoogle ScholarPubMed
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
Shifman, S, Johannesson, M, Bronstein, M, Chen, SX, Collier, DA, Craddock, NJ, Kendler, KS, Li, T, O'Donovan, M, O'Neill, FA, Owen, MJ, Walsh, D, Weinberger, DR, Sun, C, Flint, J, Darvasi, A (2008). Genome-wide association identifies a common variant in the reelin gene that increases the risk of schizophrenia only in women. PLoS Genetics 4, e28.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, 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, Yoon, JL, 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 (2009). Common variants conferring risk of schizophrenia. Nature 460, 744–747.CrossRefGoogle ScholarPubMed
Stefansson, H, Sigurdsson, E, Steinthorsdottir, V, Bjornsdottir, S, Sigmundsson, T, Ghosh, S, Brynjolfsson, J, Gunnarsdottir, S, Ivarsson, O, Chou, TT, Hjaltason, O, Birgisdottir, B, Jonsson, H, Gudnadottir, VG, Gudmundsdottir, E, Bjornsson, A, Ingvarsson, B, Ingason, A, Sigfusson, S, Hardardottir, H, Harvey, RP, Lai, D, Zhou, M, Brunner, D, Mutel, V, Gonzalo, A, Lemke, G, Sainz, J, Johannesson, G, Andresson, T, Gudbjartsson, D, Manolescu, A, Frigge, ML, Gurney, ME, Kong, A, Gulcher, JR, Petursson, H, Stefansson, K (2002). Neuregulin 1 and susceptibility to schizophrenia. American Journal of Human Genetics 71, 877–892.CrossRefGoogle ScholarPubMed
Stenzel, A, Lu, T, Koch, WA, Hampe, J, Guenther, SM, De La Vega, FM, Krawczak, M, Schreiber, S (2004). Patterns of linkage disequilibrium in the MHC region on human chromosome 6p. Human Genetics 114, 377–385.CrossRefGoogle ScholarPubMed
Straub, RE, Jiang, Y, MacLean, CJ, Ma, Y, Webb, BT, Myakishev, MV, Harris-Kerr, C, Wormley, B, Sadek, H, Kadambi, B, Cesare, AJ, Gibberman, A, Wang, X, O'Neill, FA, Walsh, D, Kendler, KS (2002). Genetic variation in the 6p22.3 gene DTNBP1, the human ortholog of the mouse dysbindin gene, is associated with schizophrenia. American Journal of Human Genetics 71, 337–348.CrossRefGoogle ScholarPubMed
Sullivan, PF, Lin, D, Tzeng, JY, van den Oord, E, Perkins, D, Stroup, TS, Wagner, M, Lee, S, Wright, FA, Zou, F, Liu, W, Downing, AM, Lieberman, J, Close, SL (2008). Genomewide association for schizophrenia in the CATIE study: results of stage 1. Molecular Psychiatry 13, 570–584.CrossRefGoogle ScholarPubMed
Vincent, JB, Petronis, A, Strong, E, Parikh, SV, Meltzer, HY, Lieberman, J, Kennedy, JL (1999). Analysis of genome-wide CAG/CTG repeats, and at SEF2-1B and ERDA1 in schizophrenia and bipolar affective disorder. Molecular Psychiatry 4, 229–234.CrossRefGoogle ScholarPubMed
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