Abstract
Schizophrenia is a severe, debilitating and common psychiatric disorder, which directly affects ∼1% of the population worldwide. Although previous studies have unequivocally shown that schizophrenia has a strong genetic component, our understanding of its pathophysiology remains limited. The precise genetic architecture of schizophrenia remains elusive and is likely to be complex. It is believed that multiple genetic variants, with each contributing a modest effect on disease risk, interact with environmental factors resulting in the phenotype. In this chapter, we summarise the main molecular genetic approaches that have been utilised in identifying susceptibility genes for schizophrenia and discuss the advantages and disadvantages of each approach. First, we detail the findings of linkage mapping in pedigrees (affected families), which analyse the co-segregation of polymorphic genetic markers with disease phenotype. Second, the contribution of targeted and genome-wide association studies, which compare differential allelic frequencies in schizophrenia cases and matched controls, is presented. Third, we discuss about the identification of susceptibility genes through analysis of chromosomal structural variation (gains and losses of genetic material). Lastly, we introduce the concept of re-sequencing, where the entire genome/exome is sequenced both in affected and unaffected individuals. This approach has the potential to provide a clarified picture of the majority of the genetic variation underlying disease pathogenesis.
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References
Abrahams BS, Geschwind DH (2008) Advances in autism genetics: on the threshold of a new neurobiology. Nat Rev Genet 9:341–355
Alarcón M, Abrahams BS, Stone JL, Duvall JA, Perederiy JV, Bomar JM, Sebat J, Wigler M, Martin CL, Ledbetter DH, Nelson SF, Cantor RM, Geschwind DH (2008) Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. Am J Hum Genet 82:150–159
Badano JL, Katsanis N (2002) Beyond Mendel: an evolving view of human genetic disease transmission. Nat Rev Genet 3:779–789
Blackwood DHR, Fordyce A, Walker MT, St Clair DM, Porteous DJ, Muir WJ (2001) Schizophrenia and affective disorders – cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: clinical and P300 findings in a family. Am J Hum Genet 69:428–433
Blouin JL, Dombroski BA, Nath SK, Lasseter VK, Wolyniec PS, Nestadt G, Thornquist M, Ullrich G, McGrath J, Kasch L, Lamacz M, Thomas MG, Gehrig C, Radhakrishna U, Snyder SE, Balk KG, Neufeld K, Swartz KL, DeMarchi N, Papadimitriou GN, Dikeos DG, Stefanis CN, Chakravarti A, Childs B, Housman DE, Kazazian HH, Antonarakis S, Pulver AE (1998) Schizophrenia susceptibility loci on chromosomes 13q32 and 8p21. Nat Genet 20:70–73
Botstein D, Risch N (2003) Discovering genotypes underlying human phenotypes: past successes for Mendelian disease, future approaches for complex disease. Nat Genet 33 Suppl:228–237
Brzustowicz LM, Hodgkinson KA, Chow EW, Honer WG, Bassett AS (2000) Location of a major susceptibility locus for familial schizophrenia on chromosome 1q21–q22. Science 288:678–682
Campion D, Flaman JM, Brice A, Hannequin D, Dubois B, Martin C, Moreau V, Charbonnier F, Didierjean O, Tardieu S, Penet C, Puel M, Pasquier F, Le Doze F, Bellis G, Calenda A, Heilig R, Martinez M, Mallet J, Bellis M, Clerget-Darpoux F, Agid Y, Frebourg T (1995) Mutations of the presenilin I gene in families with early-onset Alzheimer’s disease. Hum Mol Genet 4:2373–2377
Chowdari KV, Mirnics K, Semwal P, Wood J, Lawrence E, Bhatia T, Deshpande SN, Thelma BK, Ferrell RE, Middleton FA, Devlin B, Levitt P, Lewis DA, Nimgaonkar VL (2002) Association and linkage analyses of RGS4 polymorphisms in schizophrenia. Hum Mol Genet 11:1373–1380
Chumakov I, Blumenfeld M, Guerassimenko O, Cavarec L, Palicio M, Abderrahim H, Bougueleret L, Barry C, Tanaka H, La Rosa P, Puech A, Tahri N, Cohen-Akenine A, Delabrosse S, Lissarrague S, Picard FP, Maurice K, Essioux L, Millasseau P, Grel P, Debailleul V, Simon AM, Caterina D, Dufaure I, Malekzadeh K, Belova M, Luan JJ, Bouillot M, Sambucy JL, Primas G, Saumier M, Boubkiri N, Martin-Saumier S, Nasroune M, Peixoto H, Delaye A, Pinchot V, Bastucci M, Guillou S, Chevillon M, Sainz-Fuertes R, Meguenni S, Aurich-Costa J, Cherif D, Gimalac A, Van Duijn C, Gauvreau D, Ouellette G, Fortier I, Raelson J, Sherbatich T, Riazanskaia N, Rogaev E, Raeymaekers P, Aerssens J, Konings F, Luyten W, Macciardi F, Sham PC, Straub RE, Weinberger DR, Cohen N, Cohen D (2002) Genetic and physiological data implicating the new human gene G72 and the gene for d-amino acid oxidase in schizophrenia. Proc Natl Acad Sci USA 99:13675–13680
Clayton DG, Walker NM, Smyth DJ, Pask R, Cooper JD, Maier LM, Smink LJ, Lam AC, Ovington NR, Stevens HE, Nutland S, Howson JM, Faham M, Moorhead M, Jones HB, Falkowski M, Hardenbol P, Willis TD, Todd JA (2005) Population structure, differential bias and genomic control in a large-scale, case-control association study. Nat Genet 37:1243–1246
Conrad DF, Andrews TD, Carter NP, Hurles ME, Pritchard JK (2005) A high-resolution survey of deletion polymorphism in the human genome. Nat Genet 38:75–81
Conrad DF, Pinto D, Redon R, Feuk L, Gokcumen O, Zhang Y, Aerts J, Andrews TD, Barnes C, Campbell P, Fitzgerald T, Hu M, Ihm CH, Kristiansson K, Macarthur DG, Macdonald JR, Onyiah I, Pang AW, Robson S, Stirrups K, Valsesia A, Walter K, Wei J, The Wellcome Trust Case Control Consortium, Tyler-Smith C, Carter NP, Lee C, Scherer SW, Hurles ME (2009) Origins and functional impact of copy number variation in the human genome. Nature (Epub ahead of print, Oct 7)http://www.ncbi.nlm.nih.gov/pubmed/19812545(Accessed October 15, 2009)
Cook EH, Scherer SW (2008) Copy-number variations associated with neuropsychiatric conditions. Nature 455:919–923
Craig AM, Kang Y (2007) Neurexin–neuroligin signaling in synapse development. Curr Opin Neurobiol 17:43–52
Fatemi SH, King DP, Reutiman TJ, Folsom TD, Laurence JA, Lee S, Fan YT, Paciga SA, Conti M, Menniti FS (2008) PDE4B polymorphisms and decreased PDE4B expression are associated with schizophrenia. Schizophr Res 101:36–49
Feuk L, Carson AR, Scherer SW (2006) Structural variation in the human genome. Nat Rev Genet 7:85–97
Frazer KA, Ballinger DG, Cox DR, Hinds DA, Stuve LL, Gibbs RA, Belmont JW, Boudreau A, Hardenbol P, Leal SM, Pasternak S, Wheeler DA, Willis TD, Yu F, Yang H, Zeng C, Gao Y, Hu H, Hu W, Li C, Lin W, Liu S, Pan H, Tang X, Wang J, Wang W, Yu J, Zhang B, Zhang Q, Zhao H, Zhao H, Zhou J, Gabriel SB, Barry R, Blumenstiel B, Camargo A, Defelice M, Faggart M, Goyette M, Gupta S, Moore J, Nguyen H, Onofrio RC, Parkin M, Roy J, Stahl E, Winchester E, Ziaugra L, Altshuler D, Shen Y, Yao Z, Huang W, Chu X, He Y, Jin L, Liu Y, Shen Y, Sun W, Wang H, Wang Y, Wang Y, Xiong X, Xu L, Waye MM, Tsui SK, Xue H, Wong JT, Galver LM, Fan JB, Gunderson K, Murray SS, Oliphant AR, Chee MS, Montpetit A, Chagnon F, Ferretti V, Leboeuf M, Olivier JF, Phillips MS, Roumy S, Sallée C, Verner A, Hudson TJ, Kwok PY, Cai D, Koboldt DC, Miller RD, Pawlikowska L, Taillon-Miller P, Xiao M, Tsui LC, Mak W, Song YQ, Tam PK, Nakamura Y, Kawaguchi T, Kitamoto T, Morizono T, Nagashima A, Ohnishi Y, Sekine A, Tanaka T, Tsunoda T, Deloukas P, Bird CP, Delgado M, Dermitzakis ET, Gwilliam R, Hunt S, Morrison J, Powell D, Stranger BE, Whittaker P, Bentley DR, Daly MJ, de Bakker PI, Barrett J, Chretien YR, Maller J, McCarroll S, Patterson N, Pe’er I, Price A, Purcell S, Richter DJ, Sabeti P, Saxena R, Schaffner SF, Sham PC, Varilly P, Altshuler D, Stein LD, Krishnan L, Smith AV, Tello-Ruiz MK, Thorisson GA, Chakravarti A, Chen PE, Cutler DJ, Kashuk CS, Lin S, Abecasis GR, Guan W, Li Y, Munro HM, Qin ZS, Thomas DJ, McVean G, Auton A, Bottolo L, Cardin N, Eyheramendy S, Freeman C, Marchini J, Myers S, Spencer C, Stephens M, Donnelly P, Cardon LR, Clarke G, Evans DM, Morris AP, Weir BS, Tsunoda T, Mullikin JC, Sherry ST, Feolo M, Skol A, Zhang H, Zeng C, Zhao H, Matsuda I, Fukushima Y, Macer DR, Suda E, Rotimi CN, Adebamowo CA, Ajayi I, Aniagwu T, Marshall PA, Nkwodimmah C, Royal CD, Leppert MF, Dixon M, Peiffer A, Qiu R, Kent A, Kato K, Niikawa N, Adewole IF, Knoppers BM, Foster MW, Clayton EW, Watkin J, Gibbs RA, Belmont JW, Muzny D, Nazareth L, Sodergren E, Weinstock GM, Wheeler DA, Yakub I, Gabriel SB, Onofrio RC, Richter DJ, Ziaugra L, Birren BW, Daly MJ, Altshuler D, Wilson RK, Fulton LL, Rogers J, Burton J, Carter NP, Clee CM, Griffiths M, Jones MC, McLay K, Plumb RW, Ross MT, Sims SK, Willey DL, Chen Z, Han H, Kang L, Godbout M, Wallenburg JC, L’Archevêque P, Bellemare G, Saeki K, Wang H, An D, Fu H, Li Q, Wang Z, Wang R, Holden AL, Brooks LD, McEwen JE, Guyer MS, Wang VO, Peterson JL, Shi M, Spiegel J, Sung LM, Zacharia LF, Collins FS, Kennedy K, Jamieson R, Stewart J (2007) A second generation human haplotype map of over 3.1 million SNPs. Nature 449:851–861
Friedman JI, Vrijenhoek T, Markx S, Janssen IM, van der Vliet WA, Faas BH, Knoers NV, Cahn W, Kahn RS, Edelmann L, Davis KL, Silverman JM, Brunner HG, van Kessel AG, Wijmenga C, Ophoff RA, Veltman JA (2008) CNTNAP2 gene dosage variation is associated with schizophrenia and epilepsy. Mol Psychiatry 13:261–266
Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, DeFelice M, Lochner A, Faggart M, Liu-Cordero SN, Rotimi C, Adeyemo A, Cooper R, Ward R, Lander ES, Daly MJ, Altshuler D (2002) The structure of haplotype blocks in the human genome. Science 296:2225–2229
Gonzalez E, Kulkarni H, Bolivar H, Mangano A, Sanchez R, Catano G, Nibbs RJ, Freedman BI, Quinones MP, Bamshad MJ, Murthy KK, Rovin BH, Bradley W, Clark RA, Anderson SA, O’connell RJ, Agan BK, Ahuja SS, Bologna R, Sen L, Dolan MJ, Ahuja SK (2005) The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility. Science 307:1434–1440
Göring HH, Terwilliger JD, Blangero J (2001) Large upward bias in estimation of locus-specific effects from genomewide scans. Am J Hum Genet 69:1357–1369
Hinds DA, Stuve LL, Nilsen GB, Halperin E, Eskin E, Ballinger DG, Frazer KA, Cox DR (2005) Whole-genome patterns of common DNA variation in three human populations. Science 307:1072–1079
Hirschhorn JN, Altshuler D (2002) Once and again-issues surrounding replication in genetic association studies. J Clin Endocrinol Metab 87(10):4438–41
Hirschhorn JN, Daly MJ (2005) Genome-wide association studies for common diseases and complex traits. Nat Rev Genet 6:95–108
Ingason A, Rujescu D, Cichon S, Sigurdsson E, Sigmundsson T, Pietiläinen OP, Buizer-Voskamp JE, Strengman E, Francks C, Muglia P, Gylfason A, Gustafsson O, Olason PI, Steinberg S, Hansen T, Jakobsen KD, Rasmussen HB, Giegling I, Möller HJ, Hartmann A, Crombie C, Fraser G, Walker N, Lonnqvist J, Suvisaari J, Tuulio-Henriksson A, Bramon E, Kiemeney LA, Franke B, Murray R, Vassos E, Toulopoulou T, Mühleisen TW, Tosato S, Ruggeri M, Djurovic S, Andreassen OA, Zhang Z, Werge T, Ophoff RA; GROUP Investigators, Rietschel M, Nöthen MM, Petursson H, Stefansson H, Peltonen L, Collier D, Stefansson K, Clair DM (2009) Copy number variations of chromosome 16p13.1 region associated with schizophrenia. Mol Psychiatry (Epub ahead of print, Sept 29) Available at: http://www.ncbi.nlm.nih.gov/pubmed/19786961 (Accessed September 30, 2009)
International HapMap Consortium (2005) A haplotype map of the human genome. Nature 437:1299–1320
Ioannidis JP, Thomas G, Daly MJ (2009) Validating, augmenting and refining genome-wide association signals. Nat Rev Genet 10:318–329
Johansson I, Lundqvist E, Bertilsson L, Dahl ML, Sjöqvist F, Ingelman-Sundberg M (1993) Inherited amplification of an active gene in the cytochrome P450 CYP2D locus as a cause of ultrarapid metabolism of debrisoquine. Proc Natl Acad Sci USA 90:11825–11829
Kathiresan S, Willer CJ, Peloso GM, Demissie S, Musunuru K, Schadt EE, Kaplan L, Bennett D, Li Y, Tanaka T, Voight BF, Bonnycastle LL, Jackson AU, Crawford G, Surti A, Guiducci C, Burtt NP, Parish S, Clarke R, Zelenika D, Kubalanza KA, Morken MA, Scott LJ, Stringham HM, Galan P, Swift AJ, Kuusisto J, Bergman RN, Sundvall J, Laakso M, Ferrucci L, Scheet P, Sanna S, Uda M, Yang Q, Lunetta KL, Dupuis J, de Bakker PI, O’Donnell CJ, Chambers JC, Kooner JS, Hercberg S, Meneton P, Lakatta EG, Scuteri A, Schlessinger D, Tuomilehto J, Collins FS, Groop L, Altshuler D, Collins R, Lathrop GM, Melander O, Salomaa V, Peltonen L, Orho-Melander M, Ordovas JM, Boehnke M, Abecasis GR, Mohlke KL, Cupples LA (2009) Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet 41:56–65
Kirov G, Gumus D, Chen W, Norton N, Georgieva L, Sari M, O’Donovan MC, Erdogan F, Owen MJ, Ropers HH, Ullmann R (2008) Comparative genome hybridization suggests a role for NRXN1 and APBA2 in schizophrenia. Hum Mol Genet 17:458–465
Kruglyak L (2008) The road to genome-wide association studies. Nat Rev Genet 9:314–318
Lander ES, Schork NJ (1994) Genetic dissection of complex traits. Science 265:2037–2048
Lawson-Yuen A, Saldivar JS, Sommer S, Picker J (2008) Familial deletion within NLGN4 associated with autism and Tourette syndrome. Eur J Hum Genet 16:614–618
Lerer B, Segman RH, Hamdan A, Kanyas K, Karni O, Kohn Y, Korner M, Lanktree M, Kaadan M, Turetsky N, Yakir A, Kerem B, Macciardi F (2003) Genome scan of Arab Israeli families maps a schizophrenia susceptibility gene to chromosome 6q23 and supports a locus at chromosome 10q24. Mol Psychiatry 8:488–498
Levinson DF, Levinson MD, Segurado R, Lewis CM (2003) Genome scan meta-analysis of schizophrenia and bipolar disorder, part I: Methods and power analysis. Am J Hum Genet 73:17–33
Levy S, Sutton G, Ng PC, Feuk L, Halpern AL, Walenz BP, Axelrod N, Huang J, Kirkness EF, Denisov G, Lin Y, MacDonald JR, Pang AW, Shago M, Stockwell TB, Tsiamouri A, Bafna V, Bansal V, Kravitz SA, Busam DA, Beeson KY, McIntosh TC, Remington KA, Abril JF, Gill J, Borman J, Rogers YH, Frazier ME, Scherer SW, Strausberg RL, Venter JC (2007) The diploid genome sequence of an individual human. PLoS Biol 5:e254
Lewis CM, Levinson DF, Wise LH, DeLisi LE, Straub RE, Hovatta I, Williams NM, Schwab SG, Pulver AE, Faraone SV, Brzustowicz LM, Kaufmann CA, Garver DL, Gurling HM, Lindholm E, Coon H, Moises HW, Byerley W, Shaw SH, Mesen A, Sherrington R, O’Neill FA, Walsh D, Kendler KS, Ekelund J, Paunio T, Lönnqvist J, Peltonen L, O’Donovan MC, Owen MJ, Wildenauer DB, Maier W, Nestadt G, Blouin JL, Antonarakis SE, Mowry BJ, Silverman JM, Crowe RR, Cloninger CR, Tsuang MT, Malaspina D, Harkavy-Friedman JM, Svrakic DM, Bassett AS, Holcomb J, Kalsi G, McQuillin A, Brynjolfson J, Sigmundsson T, Petursson H, Jazin E, Zoëga T, Helgason T (2003) Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia. Am J Hum Genet 73:34–48
Li B, Leal SM (2008) Methods for detecting associations with rare variants for common diseases: application to analysis of sequence data. Am J Hum Genet 83:311–321
Li M, Li C, Guan W (2008) Evaluation of coverage variation of SNP chips for genome-wide association studies. Eur J Hum Genet 16:635–643
Lindholm E, Ekholm B, Shaw S, Jalonen P, Johansson G, Pettersson U, Sherrington R, Adolfsson R, Jazin E (2001) A schizophrenia-susceptibility locus at 6q25, in one of the world’s largest reported pedigrees. Am J Hum Genet 69:96–105
Liu H, Heath SC, Sobin C, Roos JL, Galke BL, Blundell ML, Lenane M, Robertson B, Wijsman EM, Rapoport JL, Gogos JA, Karayiorgou M (2002) Genetic variation at the 22q11 PRODH2/DGCR6 locus presents an unusual pattern and increases susceptibility to schizophrenia. Proc Natl Acad Sci USA 99:3717–3722
Lusis AJ, Pajukanta P (2008) A treasure trove for lipoprotein biology. Nat Genet 40:129–130
Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, McCarthy MI, Ramos EM, Cardon LR, Chakravarti A, Cho JH, Guttmacher AE, Kong A, Kruglyak L, Mardis E, Rotimi CN, Slatkin M, Valle D, Whittemore AS, Boehnke M, Clark AG, Eichler EE, Gibson G, Haines JL, Mackay TF, McCarroll SA, Visscher PM (2009) Finding the missing heritability of complex diseases. Nature 461:747–753
McCarroll SA (2008) Extending genome-wide association studies to copy-number variation. Hum Mol Genet 17:R135
McCarroll SA, Hadnott TN, Perry GH, Sabeti PC, Zody MC, Barrett JC, Dallaire S, Gabriel SB, Lee C, Daly MJ, Altshuler DM, International HapMap Consortium (2005) Common deletion polymorphisms in the human genome. Nat Genet 38:86–92
McCarroll SA, Kuruvilla FG, Korn JM, Cawley S, Nemesh J, Wysoker A, Shapero MH, de Bakker PI, Maller JB, Kirby A, Elliott AL, Parkin M, Hubbell E, Webster T, Mei R, Veitch J, Collins PJ, Handsaker R, Lincoln S, Nizzari M, Blume J, Jones KW, Rava R, Daly MJ, Gabriel SB, Altshuler D (2008) Integrated detection and population-genetic analysis of SNPs and copy number variation. Nat Genet 40:1166–1174
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. Nat Rev Genet 9:356–369
McCarthy SE, Makarov V, Kirov G, Addington AM, McClellan J, Yoon S, Perkins DO, Dickel DE, Kusenda M, Krastoshevsky O, Krause V, Kumar RA, Grozeva D, Malhotra D, Walsh T, Zackai EH, Kaplan P, Ganesh J, Krantz ID, Spinner NB, Roccanova P, Bhandari A, Pavon K, Lakshmi B, Leotta A, Kendall J, Lee YH, Vacic V, Gary S, Iakoucheva LM, Crow TJ, Christian SL, Lieberman JA, Stroup TS, Lehtimäki T, Puura K, Haldeman-Englert C, Pearl J, Goodell M, Willour VL, Derosse P, Steele J, Kassem L, Wolff J, Chitkara N, McMahon FJ, Malhotra AK, Potash JB, Schulze TG, Nöthen MM, Cichon S, Rietschel M, Leibenluft E, Kustanovich V, Lajonchere CM, Sutcliffe JS, Skuse D, Gill M, Gallagher L, Mendell NR, Wellcome Trust Case Control Consortium, Craddock N, Owen MJ, O’Donovan MC, Shaikh TH, Susser E, Delisi LE, Sullivan PF, Deutsch CK, Rapoport J, Levy DL, King MC, Sebat J (2009) Microduplications of 16p11.2 are associated with schizophrenia. Nat Genet 41:1223–1227
McClellan JM, Susser E, King M (2007) Schizophrenia: a common disease caused by multiple rare alleles. Br J Psychiatry 190:194–199
Millar JK, Wilson-Annan JC, Anderson S, Christie S, Taylor MS, Semple CA, Devon RS, St Clair DM, Muir WJ, Blackwood DH, Porteous DJ (2000) Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum Mol Genet 9:1415–1423
Miller RD, Phillips MS, Jo I, Donaldson MA, Studebaker JF, Addleman N, Alfisi SV, Ankener WM, Bhatti HA, Callahan CE, Carey BJ, Conley CL, Cyr JM, Derohannessian V, Donaldson RA, Elosua C, Ford SE, Forman AM, Gelfand CA, Grecco NM, Gutendorf SM, Hock CR, Hozza MJ, Hur S, In SM, Jackson DL, Jo SA, Jung SC, Kim S, Kimm K, Kloss EF, Koboldt DC, Kuebler JM, Kuo FS, Lathrop JA, Lee JK, Leis KL, Livingston SA, Lovins EG, Lundy ML, Maggan S, Minton M, Mockler MA, Morris DW, Nachtman EP, Oh B, Park C, Park CW, Pavelka N, Perkins AB, Restine SL, Sachidanandam R, Reinhart AJ, Scott KE, Shah GJ, Tate JM, Varde SA, Walters A, White JR, Yoo YK, Lee JE, Boyce-Jacino MT, Kwok PY, SNP Consortium Allele Frequency Project (2005) High-density single-nucleotide polymorphism maps of the human genome. Genomics 86:117–126
Moskvina V, Holmans P, Schmidt KM, Craddock N (2005) Design of case-controls studies with unscreened controls. Ann Hum Genet 69:566–576
Murphy KC, Jones LA, Owen MJ (1999) High rates of schizophrenia in adults with velo-cardio-facial syndrome. Arch Gen Psychiatry 56:940–945
Ng PC, Levy S, Huang J, Stockwell TB, Walenz BP, Li K, Axelrod N, Busam DA, Strausberg RL, Venter JC (2008) Genetic variation in an individual human exome. PLoS Genet 4:e1000160
Ng SB, Turner EH, Robertson PD, Flygare SD, Bigham AW, Lee C, Shaffer T, Wong M, Bhattacharjee A, Eichler EE, Bamshad M, Nickerson DA, Shendure J (2009) Targeted capture and massively parallel sequencing of 12 human exomes. Nature 461:272–276
O’Donovan MC, Williams NM, Owen MJ (2003) Recent advances in the genetics of schizophrenia. Hum Mol Genet 12 (Spec No 2):R125–R133
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, Möller 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, Nöthen 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, Molecular Genetics of Schizophrenia Collaboration (2008) Identification of loci associated with schizophrenia by genome-wide association and follow-up. Nat Genet 40:1053–1055
Owen MJ, O’Donovan MC, Gottesman II (2002) Schizophrenia. In: McGuffin P, Owen MJ, Gotesman II (eds) Psychiatric genetics and genomics. Medical Publications, Oxford, pp 247–266
Papolos DF, Faedda GL, Veit S, Goldberg R, Morrow B, Kucherlapati R, Shprintzen RJ (1996) Bipolar spectrum disorders in patients diagnosed with velo-cardio-facial syndrome: does a hemizygous deletion of chromosome 22q11 result in bipolar affective disorder? Am J Psychiatry 153:1541–1547
Pickard BS, Thomson PA, Christoforou A, Evans KL, Morris SW, Porteous DJ, Blackwood DH, Muir WJ (2007) The PDE4B gene confers sex-specific protection against schizophrenia. Psychiatr Genet 17:129–133
Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D (2006) Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38:904–909
Pritchard JK (2001) Are rare variants responsible for susceptibility to complex diseases? Am J Hum Genet 69:124–137
Pulver AE, Nestadt G, Goldberg R, Shprintzen RJ, Lamacz M, Wolyniec PS, Morrow B, Karayiorgou M, Antonarakis SE, Housman D, Kucherlapati R (1994) Psychotic illness in patients diagnosed with velo-cardio-facial syndrome and their relatives. J Nerv Ment Dis 182:476–478
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
Redon R, Ishikawa S, Fitch KR, Feuk L, Perry GH, Andrews TD, Fiegler H, Shapero MH, Carson AR, Chen W, Cho EK, Dallaire S, Freeman JL, González JR, Gratacòs M, Huang J, Kalaitzopoulos D, Komura D, MacDonald JR, Marshall CR, Mei R, Montgomery L, Nishimura K, Okamura K, Shen F, Somerville MJ, Tchinda J, Valsesia A, Woodwark C, Yang F, Zhang J, Zerjal T, Zhang J, Armengol L, Conrad DF, Estivill X, Tyler-Smith C, Carter NP, Aburatani H, Lee C, Jones KW, Scherer SW, Hurles ME (2006) Global variation in copy number in the human genome. Nature 444:444–454
Reich DE, Lander ES (2001) On the allelic spectrum of human disease. Trends Genet 17:502–510
Risch N (1990a) Linkage strategies for genetically complex traits. I. Multilocus models. Am J Hum Genet 46:222–228
Risch N (1990b) Linkage strategies for genetically complex traits. II. The power of affected relative pairs. Am J Hum Genet 46:229–241
Risch N, Merikangas K (1996) The future of genetic studies of complex human diseases. Science 273:1516–1517
Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C, Walsh T, Yamrom B, Yoon S, Krasnitz A, Kendall J, Leotta A, Pai D, Zhang R, Lee YH, Hicks J, Spence SJ, Lee AT, Puura K, Lehtimäki T, Ledbetter D, Gregersen PK, Bregman J, Sutcliffe JS, Jobanputra V, Chung W, Warburton D, King MC, Skuse D, Geschwind DH, Gilliam TC, Ye K, Wigler M (2007) Strong association of de novo copy number mutations with autism. Science 316:445–449
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
Shifman S, Bronstein M, Sternfeld M, Pisanté-Shalom A, Lev-Lehman E, Weizman A, Reznik I, Spivak B, Grisaru N, Karp L, Schiffer R, Kotler M, Strous RD, Swartz-Vanetik M, Knobler HY, Shinar E, Beckmann JS, Yakir B, Risch N, Zak NB, Darvasi A (2002) A highly significant association between a COMT haplotype and schizophrenia. Am J Hum Genet 71:1296–1302
Shih RA, Belmonte PL, Zandi PP (2004) A review of the evidence from family, twin and adoption studies for a genetic contribution to adult psychiatric disorders. Int Rev Psychiatry 16:260–283
Shprintzen RJ, Goldberg R, Golding-Kushner KJ, Marion RW (1992) Late-onset psychosis in the velo-cardio-facial syndrome. Am J Med Genet 42:141–142
Stefansson H, Rujescu D, Cichon S, Pietiläinen OP, Ingason A, Steinberg S, Fossdal R, Sigurdsson E, Sigmundsson T, Buizer-Voskamp JE, Hansen T, Jakobsen KD, Muglia P, Francks C, Matthews PM, Gylfason A, Halldorsson BV, Gudbjartsson D, Thorgeirsson TE, Sigurdsson A, Jonasdottir A, Jonasdottir A, Bjornsson A, Mattiasdottir S, Blondal T, Haraldsson M, Magnusdottir BB, Giegling I, Möller HJ, Hartmann A, Shianna KV, Ge D, Need AC, Crombie C, Fraser G, Walker N, Lonnqvist J, Suvisaari J, Tuulio-Henriksson A, Paunio T, Toulopoulou T, Bramon E, Di Forti M, Murray R, Ruggeri M, Vassos E, Tosato S, Walshe M, Li T, Vasilescu C, Mühleisen TW, Wang AG, Ullum H, Djurovic S, Melle I, Olesen J, Kiemeney LA, Franke B, GROUP, Sabatti C, Freimer NB, Gulcher JR, Thorsteinsdottir U, Kong A, Andreassen OA, Ophoff RA, Georgi A, Rietschel M, Werge T, Petursson H, Goldstein DB, Nöthen MM, Peltonen L, Collier DA, St Clair D, Stefansson K (2008) Large recurrent microdeletions associated with schizophrenia. Nature 455:232–236
Stefansson H, Ophoff RA, Steinberg S, Andreassen OA, Cichon S, Rujescu D, Werge T, Pietiläinen OP, Mors O, Mortensen PB, Sigurdsson E, Gustafsson O, Nyegaard M, Tuulio-Henriksson A, Ingason A, Hansen T, Suvisaari J, Lonnqvist J, Paunio T, Børglum AD, Hartmann A, Fink-Jensen A, Nordentoft M, Hougaard D, Norgaard-Pedersen B, Böttcher Y, Olesen J, Breuer R, Möller HJ, Giegling I, Rasmussen HB, Timm S, Mattheisen M, Bitter I, Réthelyi 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, Yoon JL, Shianna KV, Freimer NB, Cantor RM, Murray R, Kong A, Golimbet V, Carracedo A, Arango C, Costas J, Jönsson EG, Terenius L, Agartz I, Petursson H, Nöthen 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
Straub RE, MacLean CJ, O’Neill FA, Burke J, Murphy B, Duke F, Shinkwin R, Webb BT, Zhang J, Walsh D, Kendler KS (1995) A potential vulnerability locus for schizophrenia on chromosome 6p24-22: evidence for genetic heterogeneity. Nat Genet 11:287–293
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. Am J Hum Genet 71:337–348
Suarez B, Hampe C, VanEerdewegh P (1994) Problems of replicating linkage claims in psychiatry. In: Genetic approaches to mental disorders. American Psychiatric Press, Washington DC, pp 23–46
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. Mol Psychiatry 13:570–584
Terwilliger JD, Hiekkalinna T (2006) An utter refutation of the “fundamental theorem of the HapMap”. Eur J Hum Genet 14:426–437
The International Schizophrenia Consortium (2008) Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 455:237–241
The Wellcome Trust Case Control Consortium (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447:661–678
Thorisson GA, Stein LD (2003) The SNP Consortium website: past, present and future. Nucleic Acids Res 31:124–127
Tishkoff SA, Verrelli BC (2003) Patterns of human genetic diversity: implications for human evolutionary history and disease. Annu Rev Genomics Hum Genet 4:293–340
van Ommen GB (2005) Frequency of new copy number variation in humans. Nat Genet 37:333–334
Voight BF, Pritchard JK (2005) Confounding from cryptic relatedness in case-control association studies. PLoS Genet 1:e32
Walsh T, McClellan JM, McCarthy SE, Addington AM, Pierce SB, Cooper GM, Nord AS, Kusenda M, Malhotra D, Bhandari A, Stray SM, Rippey CF, Roccanova P, Makarov V, Lakshmi B, Findling RL, Sikich L, Stromberg T, Merriman B, Gogtay N, Butler P, Eckstrand K, Noory L, Gochman P, Long R, Chen Z, Davis S, Baker C, Eichler EE, Meltzer PS, Nelson SF, Singleton AB, Lee MK, Rapoport JL, King MC, Sebat J (2008) Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 320:539–543
Wang K, Li M, Hadley D, Liu R, Glessner J, Grant SF, Hakonarson H, Bucan M (2007) PennCNV: an integrated hidden Markov model designed for high-resolution copy number variation detection in whole-genome SNP genotyping data. Genome Res 17:1665–1674
Williams NM, Norton N, Williams H, Ekholm B, Hamshere ML, Lindblom Y, Chowdari KV, Cardno AG, Zammit S, Jones LA, Murphy KC, Sanders RD, McCarthy G, Gray MY, Jones G, Holmans P, Nimgaonkar V, Adolfson R, Osby U, Terenius L, Sedvall G, O’Donovan MC, Owen MJ (2003) A systematic genomewide linkage study in 353 sib pairs with schizophrenia. Am J Hum Genet 73:1355–1367
Zeggini E, Weedon MN, Lindgren CM, Frayling TM, Elliott KS, Lango H, Timpson NJ, Perry JR, Rayner NW, Freathy RM, Barrett JC, Shields B, Morris AP, Ellard S, Groves CJ, Harries LW, Marchini JL, Owen KR, Knight B, Cardon LR, Walker M, Hitman GA, Morris AD, Doney AS, Wellcome Trust Case Control Consortium (WTCCC), McCarthy MI, Hattersley AT (2007) Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 316:1336–1341
Zheng G, Freidlin B, Gastwirth JL (2006) Robust genomic control for association studies. Am J Hum Genet 78:350–356
Zollner S, Pritchard JK (2007) Overcoming the winner’s curse: estimating penetrance parameters from case-control data. Am J Hum Genet 80:605–615
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Mantripragada, K.K., Carroll, L.S., Williams, N.M. (2010). Experimental Approaches for Identifying Schizophrenia Risk Genes. In: Swerdlow, N. (eds) Behavioral Neurobiology of Schizophrenia and Its Treatment. Current Topics in Behavioral Neurosciences, vol 4. Springer, Berlin, Heidelberg. https://doi.org/10.1007/7854_2010_58
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