Hostname: page-component-8448b6f56d-cfpbc Total loading time: 0 Render date: 2024-04-16T16:07:40.174Z Has data issue: false hasContentIssue false
  • English
  • Français

Rethinking the genetic architecture of schizophrenia

Published online by Cambridge University Press:  12 April 2010

K. J. Mitchell  and
D. J. Porteous
K. J. Mitchell*
Affiliation:
Smurfit Institute of Genetics, Trinity College Dublin, Ireland
D. J. Porteous*
Affiliation:
Medical Genetics Section, University of Edinburgh Molecular Medicine Centre, Institute of Genetics and Molecular Medicine, Edinburgh, UK
*
*Address for correspondence: Dr K. J. Mitchell, Smurfit Institute of Genetics, Trinity College Dublin, Ireland. (Email: Kevin.Mitchell@tcd.ie)
(Email: David.Porteous@ed.ac.uk)
Get access Rights & Permissions [Opens in a new window]

Abstract

Background

For many years, the prevailing paradigm has stated that in each individual with schizophrenia (SZ) the genetic risk is due to a combination of many genetic variants, individually of small effect. Recent empirical data are prompting a re-evaluation of this polygenic, common disease–common variant (CDCV) model. Evidence includes a lack of the expected strong positive findings from genome-wide association studies and the concurrent discovery of many different mutations that individually strongly predispose to SZ and other psychiatric disorders. This has led some to adopt a mixed model wherein some cases are caused by polygenic mechanisms and some by single mutations. This model runs counter to a substantial body of theoretical literature that had supposedly conclusively rejected Mendelian inheritance with genetic heterogeneity. Here we ask how this discrepancy between theory and data arose and propose a rationalization of the recent evidence base.

Method

In light of recent empirical findings, we reconsider the methods and conclusions of early theoretical analyses and the explicit assumptions underlying them.

Results

We show that many of these assumptions can now be seen to be false and that the model of genetic heterogeneity is consistent with observed familial recurrence risks, endophenotype studies and other population-wide parameters.

Conclusions

We argue for a more biologically consilient mixed model that involves interactions between disease-causing and disease-modifying variants in each individual. We consider the implications of this model for moving SZ research beyond statistical associations to pathogenic mechanisms.

Keywords

Heterogeneouspolygenicschizophrenia
Type
Review Article
Information
Psychological Medicine , Volume 41 , Issue 1 , January 2011 , pp. 19 - 32
Copyright
Copyright © Cambridge University Press 2010

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Bakkaloglu, B, O'Roak, BJ, Louvi, A, Gupta, AR, Abelson, JF, Morgan, TM, Chawarska, K, Klin, A, Ercan-Sencicek, AG, Stillman, AA, Tanriover, G, Abrahams, BS, Duvall, JA, Robbins, EM, Geschwind, DH, Biederer, T, Gunel, M, Lifton, RP, State, MW (2008). Molecular cytogenetic analysis and resequencing of contactin associated protein-like 2 in autism spectrum disorders. American Journal of Human Genetics 82, 165–173.CrossRefGoogle ScholarPubMed
Ballif, BC, Theisen, A, Coppinger, J, Gowans, GC, Hersh, JH, Madan-Khetarpal, S, Schmidt, KR, Tervo, R, Escobar, LF, Friedrich, CA, McDonald, M, Campbell, L, Ming, JE, Zackai, EH, Bejjani, BA, Shaffer, LG (2008). Expanding the clinical phenotype of the 3q29 microdeletion syndrome and characterization of the reciprocal microduplication. Molecular Cytogenetics 1, 8.CrossRefGoogle ScholarPubMed
Barnett, JH, Salmond, CH, Jones, PB, Sahakian, BJ (2006). Cognitive reserve in neuropsychiatry. Psychological Medicine 36, 1053–1064.CrossRefGoogle ScholarPubMed
Blackwood, DH, Muir, WJ (2004). Clinical phenotypes associated with DISC1, a candidate gene for schizophrenia. Neurotoxicity Research 6, 35–41.CrossRefGoogle ScholarPubMed
Braff, DL, Freedman, R, Schork, NJ, Gottesman, II (2007). Deconstructing schizophrenia: an overview of the use of endophenotypes in order to understand a complex disorder. Schizophrenia Bulletin 33, 21–32.CrossRefGoogle ScholarPubMed
Brunetti-Pierri, N, Berg, JS, Scaglia, F, Belmont, J, Bacino, CA, Sahoo, T, Lalani, SR, Graham, B, Lee, B, Shinawi, M, Shen, J, Kang, SH, Pursley, A, Lotze, T, Kennedy, G, Lansky-Shafer, S, Weaver, C, Roeder, ER, Grebe, TA, Arnold, GL, Hutchison, T, Reimschisel, T, Amato, S, Geragthy, MT, Innis, JW, Obersztyn, E, Nowakowska, B, Rosengren, SS, Bader, PI, Grange, DK, Naqvi, S, Garnica, AD, Bernes, SM, Fong, CT, Summers, A, Walters, WD, Lupski, JR, Stankiewicz, P, Cheung, SW, Patel, A (2008). Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities. Nature Genetics 40, 1466–1471.CrossRefGoogle ScholarPubMed
Bucan, M, Abrahams, BS, Wang, K, Glessner, JT, Herman, EI, Sonnenblick, LI, Alvarez Retuerto, AI, Imielinski, M, Hadley, D, Bradfield, JP, Kim, C, Gidaya, NB, Lindquist, I, Hutman, T, Sigman, M, Kustanovich, V, Lajonchere, CM, Singleton, A, Kim, J, Wassink, TH, McMahon, WM, Owley, T, Sweeney, JA, Coon, H, Nurnberger, JI, Li, M, Cantor, RM, Minshew, NJ, Sutcliffe, JS, Cook, EH, Dawson, G, Buxbaum, JD, Grant, SF, Schellenberg, GD, Geschwind, DH, Hakonarson, H (2009). Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes. PLoS Genetics 5, e1000536.CrossRefGoogle Scholar
Cardno, AG, Rijsdijk, FV, Sham, PC, Murray, RM, McGuffin, P (2002). A twin study of genetic relationships between psychotic symptoms. American Journal of Psychiatry 159, 539–545.CrossRefGoogle ScholarPubMed
Carpenter, WT, Koenig, JI (2008). The evolution of drug development in schizophrenia: past issues and future opportunities. Neuropsychopharmacology 33, 2061–2079.CrossRefGoogle ScholarPubMed
Cheng, MC, Chen, CH (2007). Identification of rare mutations of synaptogyrin 1 gene in patients with schizophrenia. Journal of Psychiatric Research 41, 1027–1031.CrossRefGoogle ScholarPubMed
Chubb, JE, Bradshaw, NJ, Soares, DC, Porteous, DJ, Millar, JK (2008). The DISC locus in psychiatric illness. Molecular Psychiatry 13, 36–64.CrossRefGoogle ScholarPubMed
Cohen, JC, Kiss, RS, Pertsemlidis, A, Marcel, YL, McPherson, R, Hobbs, HH (2004). Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science 305, 869–872.CrossRefGoogle ScholarPubMed
Crow, JF (2000). The origins, patterns and implications of human spontaneous mutation. Nature Reviews Genetics 1, 40–47.CrossRefGoogle ScholarPubMed
Dempster, ER, Lerner, IM (1950). Heritability of threshold characters. Genetics 35, 212–236.CrossRefGoogle ScholarPubMed
Elia, J, Gai, X, Xie, HM, Perin, JC, Geiger, E, Glessner, JT, D'Arcy, M, Deberardinis, R, Frackelton, E, Kim, C, Lantieri, F, Muganga, BM, Wang, L, Takeda, T, Rappaport, EF, Grant, SF, Berrettini, W, Devoto, M, Shaikh, TH, Hakonarson, H, White, PS (2009). Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes. Molecular Psychiatry Published online: 23 June 2009. doi:10.1038/mp.2009.57.Google ScholarPubMed
Erlenmeyer-Kimling, L, Rock, D, Roberts, SA, Janal, M, Kestenbaum, C, Cornblatt, B, Adamo, UH, Gottesman, II (2000). Attention, memory, and motor skills as childhood predictors of schizophrenia-related psychoses: the New York High-Risk Project. American Journal of Psychiatry 157, 1416–1422.CrossRefGoogle ScholarPubMed
Frazer, KA, Murray, SS, Schork, NJ, Topol, EJ (2009). Human genetic variation and its contribution to complex traits. Nature Reviews Genetics 10, 241–251.CrossRefGoogle ScholarPubMed
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. Molecular Psychiatry 13, 261–266.CrossRefGoogle Scholar
Funayama, M, Li, Y, Tsoi, TH, Lam, CW, Ohi, T, Yazawa, S, Uyama, E, Djaldetti, R, Melamed, E, Yoshino, H, Imamichi, Y, Takashima, H, Nishioka, K, Sato, K, Tomiyama, H, Kubo, S, Mizuno, Y, Hattori, N (2008). Familial Parkinsonism with digenic parkin and PINK1 mutations. Movement Disorders 23, 1461–1465.CrossRefGoogle ScholarPubMed
Girirajan, S, Rosenfeld, JA, Cooper, GM, Antonacci, F, Siswara, P, Itsara, A, Vives, L, Walsh, T, McCarthy, SE, Baker, C, Mefford, HC, Kidd, JM, Browning, SR, Browning, BL, Dickel, DE, Levy, DL, Ballif, BC, Platky, K, Farber, DM, Gowans, GC, Wetherbee, JJ, Asamoah, A, Weaver, DD, Mark, PR, Dickerson, J, Garg, BP, Ellingwood, SA, Smith, R, Banks, VC, Smith, W, McDonald, MT, Hoo, JJ, French, BN, Hudson, C, Johnson, JP, Ozmore, JR, Moeschler, JB, Surti, U, Escobar, LF, El-Khechen, D, Gorski, JL, Kussmann, J, Salbert, B, Lacassie, Y, Biser, A, McDonald-McGinn, DM, Zackai, EH, Deardorff, MA, Shaikh, TH, Haan, E, Friend, KL, Fichera, M, Romano, C, Gecz, J, DeLisi, LE, Sebat, J, King, MC, Shaffer, LG, Eichler, EE (2010). A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay. Nature Genetics 42, 203–209.CrossRefGoogle ScholarPubMed
Glessner, JT, Wang, K, Cai, G, Korvatska, O, Kim, CE, Wood, S, Zhang, H, Estes, A, Brune, CW, Bradfield, JP, Imielinski, M, Frackelton, EC, Reichert, J, Crawford, EL, Munson, J, Sleiman, PM, Chiavacci, R, Annaiah, K, Thomas, K, Hou, C, Glaberson, W, Flory, J, Otieno, F, Garris, M, Soorya, L, Klei, L, Piven, J, Meyer, KJ, Anagnostou, E, Sakurai, T, Game, RM, Rudd, DS, Zurawiecki, D, McDougle, CJ, Davis, LK, Miller, J, Posey, DJ, Michaels, S, Kolevzon, A, Silverman, JM, Bernier, R, Levy, SE, Schultz, RT, Dawson, G, Owley, T, McMahon, WM, Wassink, TH, Sweeney, JA, Nurnberger, JI, Coon, H, Sutcliffe, JS, Minshew, NJ, Grant, SF, Bucan, M, Cook, EH, Buxbaum, JD, Devlin, B, Schellenberg, GD, Hakonarson, H (2009). Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature 459, 569–573.CrossRefGoogle ScholarPubMed
Goldstein, DB (2009). Common genetic variation and human traits. New England Journal of Medicine 360, 1696–1698.CrossRefGoogle ScholarPubMed
Gottesman, II, Gould, TD (2003). The endophenotype concept in psychiatry: etymology and strategic intentions. American Journal of Psychiatry 160, 636–645.CrossRefGoogle ScholarPubMed
Gottesman, II, Laursen, TM, Bertelsen, A, Mortensen, PB (2010). Severe mental disorders in offspring with 2 psychiatrically ill parents. Archives of General Psychiatry 67, 252–257.CrossRefGoogle ScholarPubMed
Gottesman, II, Shields, J (1967). A polygenic theory of schizophrenia. Proceedings of the National Academy of Sciences USA 58, 199–205.CrossRefGoogle ScholarPubMed
Gregory, I (1960). Genetic factors in schizophrenia. American Journal of Psychiatry 116, 961–972.CrossRefGoogle ScholarPubMed
Guilmatre, A, Dubourg, C, Mosca, AL, Legallic, S, Goldenberg, A, Drouin-Garraud, V, Layet, V, Rosier, A, Briault, S, Bonnet-Brilhault, F, Laumonnier, F, Odent, S, Le Vacon, G, Joly-Helas, G, David, V, Bendavid, C, Pinoit, JM, Henry, C, Impallomeni, C, Germano, E, Tortorella, G, Di Rosa, G, Barthelemy, C, Andres, C, Faivre, L, Frebourg, T, Saugier Veber, P, Campion, D (2009). Recurrent rearrangements in synaptic and neurodevelopmental genes and shared biologic pathways in schizophrenia, autism, and mental retardation. Archives of General Psychiatry 66, 947–956.CrossRefGoogle ScholarPubMed
Hannes, FD, Sharp, AJ, Mefford, HC, de Ravel, T, Ruivenkamp, CA, Breuning, MH, Fryns, JP, Devriendt, K, Van Buggenhout, G, Vogels, A, Stewart, H, Hennekam, RC, Cooper, GM, Regan, R, Knight, SJ, Eichler, EE, Vermeesch, JR (2009). Recurrent reciprocal deletions and duplications of 16p13.11: the deletion is a risk factor for MR/MCA while the duplication may be a rare benign variant. Journal of Medical Genetics 46, 223–232.CrossRefGoogle ScholarPubMed
International Schizophrenia Consortium (2008). Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 455, 237–241.CrossRefGoogle Scholar
James, JW (1971). Frequency in relatives for an all-or-none trait. Annals of Human Genetics 35, 47–49.CrossRefGoogle ScholarPubMed
Ji, W, Foo, JN, O'Roak, BJ, Zhao, H, Larson, MG, Simon, DB, Newton-Cheh, C, State, MW, Levy, D, Lifton, RP (2008). Rare independent mutations in renal salt handling genes contribute to blood pressure variation. Nature Genetics 40, 592–599.CrossRefGoogle ScholarPubMed
Kacser, H, Burns, JA (1981). The molecular basis of dominance. Genetics 97, 639–666.CrossRefGoogle ScholarPubMed
Kamiya, A, Tan, PL, Kubo, K, Engelhard, C, Ishizuka, K, Kubo, A, Tsukita, S, Pulver, AE, Nakajima, K, Cascella, NG, Katsanis, N, Sawa, A (2008). Recruitment of PCM1 to the centrosome by the cooperative action of DISC1 and BBS4: a candidate for psychiatric illnesses. Archives of General Psychiatry 65, 996–1006.CrossRefGoogle Scholar
Keller, MC, Miller, G (2006). Resolving the paradox of common, harmful, heritable mental disorders: which evolutionary genetic models work best? Behavioral and Brain Sciences 29, 385–404; discussion 405–452.CrossRefGoogle ScholarPubMed
Kendler, KS, Kidd, KK (1986). Recurrence risks in an oligogenic threshold model: the effect of alterations in allele frequency. Annals of Human Genetics 50, 83–91.CrossRefGoogle Scholar
Kerszberg, M (2004). Noise, delays, robustness, canalization and all that. Current Opinion in Genetics and Development 14, 440–445.CrossRefGoogle Scholar
Kinney, DK, Teixeira, P, Hsu, D, Napoleon, SC, Crowley, DJ, Miller, A, Hyman, W, Huang, E (2009). Relation of schizophrenia prevalence to latitude, climate, fish consumption, infant mortality, and skin color: a role for prenatal vitamin D deficiency and infections? Schizophrenia Bulletin 35, 582–595.CrossRefGoogle ScholarPubMed
Kirov, G, Grozeva, D, Norton, N, Ivanov, D, Mantripragada, KK, Holmans, P, Craddock, N, Owen, MJ, O'Donovan, MC (2009). Support for the involvement of large copy number variants in the pathogenesis of schizophrenia. Human Molecular Genetics 18, 1497–1503.CrossRefGoogle ScholarPubMed
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. Human Molecular Genetics 17, 458–465.CrossRefGoogle ScholarPubMed
Kitano, H (2004). Biological robustness. Nature Reviews Genetics 5, 826–837.CrossRefGoogle ScholarPubMed
Knight, HM, Pickard, BS, Maclean, A, Malloy, MP, Soares, DC, McRae, AF, Condie, A, White, A, Hawkins, W, McGhee, K, van Beck, M, Macintyre, DJ, Starr, JM, Deary, IJ, Visscher, PM, Porteous, DJ, Cannon, RE, St Clair, D, Muir, WJ, Blackwood, DH (2009). A cytogenetic abnormality and rare coding variants identify ABCA13 as a candidate gene in schizophrenia, bipolar disorder, and depression. American Journal of Human Genetics 85, 833–846.CrossRefGoogle ScholarPubMed
Kryukov, GV, Pennacchio, LA, Sunyaev, SR (2007). Most rare missense alleles are deleterious in humans: implications for complex disease and association studies. American Journal of Human Genetics 80, 727–739.CrossRefGoogle ScholarPubMed
Lichtenstein, P, Yip, BH, Bjork, C, Pawitan, Y, Cannon, TD, Sullivan, PF, Hultman, CM (2009). Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet 373, 234–239.CrossRefGoogle ScholarPubMed
Lupski, JR (2007). Genomic rearrangements and sporadic disease. Nature Genetics 39, S43–S47.CrossRefGoogle ScholarPubMed
Mah, S, Nelson, MR, Delisi, LE, Reneland, RH, Markward, N, James, MR, Nyholt, DR, Hayward, N, Handoko, H, Mowry, B, Kammerer, S, Braun, A (2006). Identification of the semaphorin receptor PLXNA2 as a candidate for susceptibility to schizophrenia. Molecular Psychiatry 11, 471–478.CrossRefGoogle ScholarPubMed
Malaspina, D, Harlap, S, Fennig, S, Heiman, D, Nahon, D, Feldman, D, Susser, ES (2001). Advancing paternal age and the risk of schizophrenia. Archives of General Psychiatry 58, 361–367.CrossRefGoogle ScholarPubMed
Marshall, CR, Noor, A, Vincent, JB, Lionel, AC, Feuk, L, Skaug, J, Shago, M, Moessner, R, Pinto, D, Ren, Y, Thiruvahindrapduram, B, Fiebig, A, Schreiber, S, Friedman, J, Ketelaars, CE, Vos, YJ, Ficicioglu, C, Kirkpatrick, S, Nicolson, R, Sloman, L, Summers, A, Gibbons, CA, Teebi, A, Chitayat, D, Weksberg, R, Thompson, A, Vardy, C, Crosbie, V, Luscombe, S, Baatjes, R, Zwaigenbaum, L, Roberts, W, Fernandez, B, Szatmari, P, Scherer, SW (2008). Structural variation of chromosomes in autism spectrum disorder. American Journal of Human Genetics 82, 477–488.CrossRefGoogle ScholarPubMed
McClellan, JM, Susser, E, King, MC (2007). Schizophrenia: a common disease caused by multiple rare alleles. British Journal of Psychiatry 190, 194–199.CrossRefGoogle ScholarPubMed
McGue, M, Gottesman, II, Rao, DC (1985). Resolving genetic models for the transmission of schizophrenia. Genetic Epidemiology 2, 99–110.CrossRefGoogle ScholarPubMed
Mefford, HC, Cooper, GM, Zerr, T, Smith, JD, Baker, C, Shafer, N, Thorland, EC, Skinner, C, Schwartz, CE, Nickerson, DA, Eichler, EE (2009). A method for rapid, targeted CNV genotyping identifies rare variants associated with neurocognitive disease. Genome Research 19, 1579–1585.CrossRefGoogle ScholarPubMed
Mefford, HC, Sharp, AJ, Baker, C, Itsara, A, Jiang, Z, Buysse, K, Huang, S, Maloney, VK, Crolla, JA, Baralle, D, Collins, A, Mercer, C, Norga, K, de Ravel, T, Devriendt, K, Bongers, EM, de Leeuw, N, Reardon, W, Gimelli, S, Bena, F, Hennekam, RC, Male, A, Gaunt, L, Clayton-Smith, J, Simonic, I, Park, SM, Mehta, SG, Nik-Zainal, S, Woods, CG, Firth, HV, Parkin, G, Fichera, M, Reitano, S, Lo Giudice, M, Li, KE, Casuga, I, Broomer, A, Conrad, B, Schwerzmann, M, Raber, L, Gallati, S, Striano, P, Coppola, A, Tolmie, JL, Tobias, ES, Lilley, C, Armengol, L, Spysschaert, Y, Verloo, P, De Coene, A, Goossens, L, Mortier, G, Speleman, F, van Binsbergen, E, Nelen, MR, Hochstenbach, R, Poot, M, Gallagher, L, Gill, M, McClellan, J, King, MC, Regan, R, Skinner, C, Stevenson, RE, Antonarakis, SE, Chen, C, Estivill, X, Menten, B, Gimelli, G, Gribble, S, Schwartz, S, Sutcliffe, JS, Walsh, T, Knight, SJ, Sebat, J, Romano, C, Schwartz, CE, Veltman, JA, de Vries, BB, Vermeesch, JR, Barber, JC, Willatt, L, Tassabehji, M, Eichler, EE (2008). Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. New England Journal of Medicine 359, 1685–1699.CrossRefGoogle ScholarPubMed
Merikangas, KR (1982). Assortative mating for psychiatric disorders and psychological traits. Archives of General Psychiatry 39, 1173–1180.CrossRefGoogle ScholarPubMed
Millar, JK, Pickard, BS, Mackie, S, James, R, Christie, S, Buchanan, SR, Malloy, MP, Chubb, JE, Huston, E, Baillie, GS, Thomson, PA, Hill, EV, Brandon, NJ, Rain, JC, Camargo, LM, Whiting, PJ, Houslay, MD, Blackwood, DH, Muir, WJ, Porteous, DJ (2005). DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling. Science 310, 1187–1191.CrossRefGoogle ScholarPubMed
Millar, JK, Wilson-Annan, JC, Anderson, S, Christie, S, Taylor, MS, Semple, CA, Devon, RS, Clair, DM, Muir, WJ, Blackwood, DH, Porteous, DJ (2000). Disruption of two novel genes by a translocation co-segregating with schizophrenia. Human Molecular Genetics 9, 1415–1423.CrossRefGoogle ScholarPubMed
Miller, DT, Shen, Y, Weiss, LA, Korn, J, Anselm, I, Bridgemohan, C, Cox, GF, Dickinson, H, Gentile, J, Harris, DJ, Hegde, V, Hundley, R, Khwaja, O, Kothare, S, Luedke, C, Nasir, R, Poduri, A, Prasad, K, Raffalli, P, Reinhard, A, Smith, SE, Sobeih, MM, Soul, JS, Stoler, J, Takeoka, M, Tan, WH, Thakuria, J, Wolff, R, Yusupov, R, Gusella, JF, Daly, MJ, Wu, BL (2009). Microdeletion/duplication at 15q13.2q13.3 among individuals with features of autism and other neuropsychiatric disorders. Journal of Medical Genetics 46, 242–248.CrossRefGoogle ScholarPubMed
Mitchell, KJ (2007). The genetics of brain wiring: from molecule to mind. PLoS Biology 5, e113.CrossRefGoogle ScholarPubMed
Nadeau, JH (2001). Modifier genes in mice and humans. Nature Reviews Genetics 2, 165–174.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
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 Genetics 4, e1000160.CrossRefGoogle Scholar
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
O'Rourke, DH, Gottesman, II, Suarez, BK, Rice, J, Reich, T (1982). Refutation of the general single-locus model for the etiology of schizophrenia. American Journal of Human Genetics 34, 630–649.Google ScholarPubMed
Owens, DG, Johnstone, EC (2006). Precursors and prodromata of schizophrenia: findings from the Edinburgh High Risk Study and their literature context. Psychological Medicine 36, 1501–1514.CrossRefGoogle ScholarPubMed
Park, JP, Moeschler, JB, Berg, SZ, Wurster-Hill, DH (1991). Schizophrenia and mental retardation in an adult male with a de novo interstitial deletion 9(q32q34.1). Journal of Medical Genetics 28, 282–283.CrossRefGoogle Scholar
Pickard, BS, Hollox, EJ, Malloy, MP, Porteous, DJ, Blackwood, DH, Armour, JA, Muir, WJ (2004). A 4q35.2 subtelomeric deletion identified in a screen of patients with co-morbid psychiatric illness and mental retardation. BMC Medical Genetics 5, 21.CrossRefGoogle Scholar
Pickard, BS, Malloy, MP, Christoforou, A, Thomson, PA, Evans, KL, Morris, SW, Hampson, M, Porteous, DJ, Blackwood, DH, Muir, WJ (2006). Cytogenetic and genetic evidence supports a role for the kainate-type glutamate receptor gene, GRIK4, in schizophrenia and bipolar disorder. Molecular Psychiatry 11, 847–857.CrossRefGoogle ScholarPubMed
Pickard, BS, Malloy, MP, Porteous, DJ, Blackwood, DH, Muir, WJ (2005). Disruption of a brain transcription factor, NPAS3, is associated with schizophrenia and learning disability. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 136B, 26–32.CrossRefGoogle ScholarPubMed
Porteous, D (2008). Genetic causality in schizophrenia and bipolar disorder: out with the old and in with the new. Current Opinion in Genetics and Development 18, 229–234.CrossRefGoogle ScholarPubMed
Prasad, KM, Sanders, R, Sweeney, J, Montrose, D, Diwadkar, V, Dworakowski, D, Miewald, J, Keshavan, M (2009). Neurological abnormalities among offspring of persons with schizophrenia: relation to premorbid psychopathology. Schizophrenia Research 108, 163–169.CrossRefGoogle ScholarPubMed
Psychiatric GWAS Consortium Steering Committee (2009). A framework for interpreting genome-wide association studies of psychiatric disorders. Molecular Psychiatry 14, 10–17.CrossRefGoogle Scholar
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
Qin, P, Xu, H, Laursen, TM, Vestergaard, M, Mortensen, PB (2005). Risk for schizophrenia and schizophrenia-like psychosis among patients with epilepsy: population based cohort study. British Medical Journal 331, 23.CrossRefGoogle ScholarPubMed
Raychaudhuri, S, Plenge, RM, Rossin, EJ, Ng, AC, Purcell, SM, Sklar, P, Scolnick, EM, Xavier, RJ, Altshuler, D, Daly, MJ (2009). Identifying relationships among genomic disease regions: predicting genes at pathogenic SNP associations and rare deletions. PLoS Genetics 5, e1000534.CrossRefGoogle ScholarPubMed
Reich, DE, Lander, ES (2001). On the allelic spectrum of human disease. Trends in Genetics 17, 502–510.CrossRefGoogle ScholarPubMed
Riley, B, Asherson, PJ, McGuffin, P (2003). Genetics and schizophrenia. In Schizophrenia (ed. Hirsch and, S. R.Weinberger, D. R.), pp. 251–276. Wiley-Blackwell: Malden, MA.CrossRefGoogle Scholar
Risch, N (1990 a). Genetic linkage and complex diseases, with special reference to psychiatric disorders. Genetic Epidemiology 7, 3–16; discussion 17–45.CrossRefGoogle ScholarPubMed
Risch, N (1990 b). Linkage strategies for genetically complex traits. I. Multilocus models. American Journal of Human Genetics 46, 222–228.Google ScholarPubMed
Risch, N, Baron, M (1984). Segregation analysis of schizophrenia and related disorders. American Journal of Human Genetics 36, 1039–1059.Google ScholarPubMed
Risch, N, Merikangas, K (1996). The future of genetic studies of complex human diseases. Science 273, 1516–1517.CrossRefGoogle ScholarPubMed
Rodriguez-Santiago, B, Brunet, A, Sobrino, B, Serra-Juhe, C, Flores, R, Armengol, L, Vilella, E, Gabau, E, Guitart, M, Guillamat, R, Martorell, L, Valero, J, Gutierrez-Zotes, A, Labad, A, Carracedo, A, Estivill, X, Perez-Jurado, LA (2009). Association of common copy number variants at the glutathione S-transferase genes and rare novel genomic changes with schizophrenia. Molecular Psychiatry. Published online: 16 June 2009. doi:10.1038/mp.2009.53.Google ScholarPubMed
Rujescu, D, Ingason, A, Cichon, S, Pietilainen, OP, Barnes, MR, Toulopoulou, T, Picchioni, M, Vassos, E, Ettinger, U, Bramon, E, Murray, R, Ruggeri, M, Tosato, S, Bonetto, C, Steinberg, S, Sigurdsson, E, Sigmundsson, T, Petursson, H, Gylfason, A, Olason, PI, Hardarsson, G, Jonsdottir, GA, Gustafsson, O, Fossdal, R, Giegling, I, Moller, HJ, Hartmann, AM, Hoffmann, P, Crombie, C, Fraser, G, Walker, N, Lonnqvist, J, Suvisaari, J, Tuulio-Henriksson, A, Djurovic, S, Melle, I, Andreassen, OA, Hansen, T, Werge, T, Kiemeney, LA, Franke, B, Veltman, J, Buizer-Voskamp, JE, Sabatti, C, Ophoff, RA, Rietschel, M, Nothen, MM, Stefansson, K, Peltonen, L, St Clair, D, Stefansson, H, Collier, DA (2009). Disruption of the neurexin 1 gene is associated with schizophrenia. Human Molecular Genetics 18, 988–996.CrossRefGoogle ScholarPubMed
Saperstein, AM, Fuller, RL, Avila, MT, Adami, H, McMahon, RP, Thaker, GK, Gold, JM (2006). Spatial working memory as a cognitive endophenotype of schizophrenia: assessing risk for pathophysiological dysfunction. Schizophrenia Bulletin 32, 498–506.CrossRefGoogle ScholarPubMed
Sebat, J, Lakshmi, B, Troge, J, Alexander, J, Young, J, Lundin, P, Maner, S, Massa, H, Walker, M, Chi, M, Navin, N, Lucito, R, Healy, J, Hicks, J, Ye, K, Reiner, A, Gilliam, TC, Trask, B, Patterson, N, Zetterberg, A, Wigler, M (2004). Large-scale copy number polymorphism in the human genome. Science 305, 525–528.CrossRefGoogle ScholarPubMed
Sebat, J, Levy, DL, McCarthy, SE (2009). Rare structural variants in schizophrenia: one disorder, multiple mutations; one mutation, multiple disorders. Trends in Genetics 25, 528–535.CrossRefGoogle ScholarPubMed
Shao, H, Burrage, LC, Sinasac, DS, Hill, AE, Ernest, SR, O'Brien, W, Courtland, HW, Jepsen, KJ, Kirby, A, Kulbokas, EJ, Daly, MJ, Broman, KW, Lander, ES, Nadeau, JH (2008). Genetic architecture of complex traits: large phenotypic effects and pervasive epistasis. Proceedings of the National Academy of Sciences USA 105, 19910–19914.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
Shi, YY, He, G, Zhang, Z, Tang, W, Zhang, Jr. J, Zhao, Q, Zhang, Sr. J, Li, XW, Xi, ZR, Fang, C, Zhao, XZ, Feng, GY, He, L (2008). A study of rare structural variants in schizophrenia patients and normal controls from Chinese Han population. Molecular Psychiatry 13, 911–913.CrossRefGoogle ScholarPubMed
Siegal, ML, Bergman, A (2002). Waddington's canalization revisited: developmental stability and evolution. Proceedings of the National Academy of Sciences USA 99, 10528–10532.CrossRefGoogle ScholarPubMed
Song, W, Li, W, Feng, J, Heston, LL, Scaringe, WA, Sommer, SS (2008). Identification of high risk DISC1 structural variants with a 2% attributable risk for schizophrenia. Biochemical and Biophysical Research Communications 367, 700–706.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, Rujescu, D, Cichon, S, Pietilainen, 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, Bjornsson, A, Mattiasdottir, S, Blondal, T, Haraldsson, M, Magnusdottir, BB, Giegling, I, Moller, 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, Muhleisen, TW, Wang, AG, Ullum, H, Djurovic, S, Melle, I, Olesen, J, Kiemeney, LA, Franke, B, Sabatti, C, Freimer, NB, Gulcher, JR, Thorsteinsdottir, U, Kong, A, Andreassen, OA, Ophoff, RA, Georgi, A, Rietschel, M, Werge, T, Petursson, H, Goldstein, DB, Nothen, MM, Peltonen, L, Collier, DA, St Clair, D, Stefansson, K (2008). Large recurrent microdeletions associated with schizophrenia. Nature 455, 232–236.CrossRefGoogle ScholarPubMed
Steinhausen, HC, Foldager, L, Perto, G, Munk-Jorgensen, P (2009). Family aggregation of mental disorders in the nationwide Danish three generation study. European Archives of Psychiatry and Clinical Neuroscience 259, 270–277.CrossRefGoogle ScholarPubMed
Steinlechner, S, Stahlberg, J, Volkel, B, Djarmati, A, Hagenah, J, Hiller, A, Hedrich, K, Konig, I, Klein, C, Lencer, R (2007). Co-occurrence of affective and schizophrenia spectrum disorders with PINK1 mutations. Journal of Neurology, Neurosurgery, and Psychiatry 78, 532–535.CrossRefGoogle ScholarPubMed
Tandon, R, Keshavan, MS, Nasrallah, HA (2008). Schizophrenia, ‘just the facts’ what we know in 2008. 2. Epidemiology and etiology. Schizophrenia Research 102, 1–18.CrossRefGoogle ScholarPubMed
Tsuang, MT, Bucher, KD, Fleming, JA (1982). Testing the monogenic theory of schizophrenia: an application of segregation analysis to blind family study data. British Journal of Psychiatry 140, 595–599.CrossRefGoogle ScholarPubMed
Turetsky, BI, Greenwood, TA, Olincy, A, Radant, AD, Braff, DL, Cadenhead, KS, Dobie, DJ, Freedman, R, Green, MF, Gur, RE, Gur, RC, Light, GA, Mintz, J, Nuechterlein, KH, Schork, NJ, Seidman, LJ, Siever, LJ, Silverman, JM, Stone, WS, Swerdlow, NR, Tsuang, DW, Tsuang, MT, Calkins, ME (2008). Abnormal auditory N100 amplitude: a heritable endophenotype in first-degree relatives of schizophrenia probands. Biological Psychiatry 64, 1051–1059.CrossRefGoogle ScholarPubMed
Tyson, C, Harvard, C, Locker, R, Friedman, JM, Langlois, S, Lewis, ME, Van Allen, M, Somerville, M, Arbour, L, Clarke, L, McGilivray, B, Yong, SL, Siegel-Bartel, J, Rajcan-Separovic, E (2005). Submicroscopic deletions and duplications in individuals with intellectual disability detected by array-CGH. American Journal of Medical Genetics. Part A 139, 173–185.CrossRefGoogle ScholarPubMed
van Bon, BW, Mefford, HC, Menten, B, Koolen, DA, Sharp, AJ, Nillesen, WM, Innis, JW, de Ravel, TJ, Mercer, CL, Fichera, M, Stewart, H, Connell, LE, Ounap, K, Lachlan, K, Castle, B, Van der Aa, N, van Ravenswaaij, C, Nobrega, MA, Serra-Juhe, C, Simonic, I, de Leeuw, N, Pfundt, R, Bongers, EM, Baker, C, Finnemore, P, Huang, S, Maloney, VK, Crolla, JA, van Kalmthout, M, Elia, M, Vandeweyer, G, Fryns, JP, Janssens, S, Foulds, N, Reitano, S, Smith, K, Parkel, S, Loeys, B, Woods, CG, Oostra, A, Speleman, F, Pereira, AC, Kurg, A, Willatt, L, Knight, SJ, Vermeesch, JR, Romano, C, Barber, JC, Mortier, G, Perez-Jurado, LA, Kooy, F, Brunner, HG, Eichler, EE, Kleefstra, T, de Vries, BB (2009). Further delineation of the 15q13 microdeletion and duplication syndromes: a clinical spectrum varying from non-pathogenic to a severe outcome. Journal of Medical Genetics 46, 511–523.CrossRefGoogle ScholarPubMed
Verkerk, AJ, Mathews, CA, Joosse, M, Eussen, BH, Heutink, P, Oostra, BA (2003). CNTNAP2 is disrupted in a family with Gilles de la Tourette syndrome and obsessive compulsive disorder. Genomics 82, 1–9.CrossRefGoogle Scholar
Verma, R, Chauhan, C, Saleem, Q, Gandhi, C, Jain, S, Brahmachari, SK (2004). A nonsense mutation in the synaptogyrin 1 gene in a family with schizophrenia. Biological Psychiatry 55, 196–199.CrossRefGoogle Scholar
Vrijenhoek, T, Buizer-Voskamp, JE, van der Stelt, I, Strengman, E, Sabatti, C, Geurts van Kessel, A, Brunner, HG, Ophoff, RA, Veltman, JA (2008). Recurrent CNVs disrupt three candidate genes in schizophrenia patients. American Journal of Human Genetics 83, 504–510.CrossRefGoogle ScholarPubMed
Waddington, CH (1959). Canalization of development and genetic assimilation of acquired characters. Nature 183, 1654–1655.CrossRefGoogle ScholarPubMed
Waddington, JL, Corvin, AP, Donohoe, G, O'Tuathaigh, CM, Mitchell, KJ, Gill, M (2007). Functional genomics and schizophrenia: endophenotypes and mutant models. Psychiatric Clinics of North America 30, 365–399.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Weiss, LA, Shen, Y, Korn, JM, Arking, DE, Miller, DT, Fossdal, R, Saemundsen, E, Stefansson, H, Ferreira, MA, Green, T, Platt, OS, Ruderfer, DM, Walsh, CA, Altshuler, D, Chakravarti, A, Tanzi, RE, Stefansson, K, Santangelo, SL, Gusella, JF, Sklar, P, Wu, BL, Daly, MJ (2008). Association between microdeletion and microduplication at 16p11.2 and autism. New England Journal of Medicine 358, 667–675.CrossRefGoogle ScholarPubMed
Wheeler, DA, Srinivasan, M, Egholm, M, Shen, Y, Chen, L, McGuire, A, He, W, Chen, YJ, Makhijani, V, Roth, GT, Gomes, X, Tartaro, K, Niazi, F, Turcotte, CL, Irzyk, GP, Lupski, JR, Chinault, C, Song, XZ, Liu, Y, Yuan, Y, Nazareth, L, Qin, X, Muzny, DM, Margulies, M, Weinstock, GM, Gibbs, RA, Rothberg, JM (2008). The complete genome of an individual by massively parallel DNA sequencing. Nature 452, 872–876.CrossRefGoogle ScholarPubMed
Wohl, M, Gorwood, P (2007). Paternal ages below or above 35 years old are associated with a different risk of schizophrenia in the offspring. European Psychiatry 22, 22–26.CrossRefGoogle ScholarPubMed
Woodberry, KA, Giuliano, AJ, Seidman, LJ (2008). Premorbid IQ in schizophrenia: a meta-analytic review. American Journal of Psychiatry 165, 579–587.CrossRefGoogle ScholarPubMed
Woolf, CM (1997). Does the genotype for schizophrenia often remain unexpressed because of canalization and stochastic events during development? Psychological Medicine 27, 659–668.CrossRefGoogle ScholarPubMed
Xu, B, Roos, JL, Levy, S, van Rensburg, EJ, Gogos, JA, Karayiorgou, M (2008). Strong association of de novo copy number mutations with sporadic schizophrenia. Nature Genetics 40, 880–885.CrossRefGoogle ScholarPubMed
Xu, B, Woodroffe, A, Rodriguez-Murillo, L, Roos, JL, van Rensburg, EJ, Abecasis, GR, Gogos, JA, Karayiorgou, M (2009). Elucidating the genetic architecture of familial schizophrenia using rare copy number variant and linkage scans. Proceedings of the National Academy of Sciences USA 106, 16746–16751.CrossRefGoogle ScholarPubMed