Hostname: page-component-7c8c6479df-27gpq Total loading time: 0 Render date: 2024-03-28T08:23:38.844Z Has data issue: false hasContentIssue false

Dissecting the many genetic faces of schizophrenia

Published online by Cambridge University Press:  11 April 2011

Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

Recent genome-wide association studies in schizophrenia have provided strongest evidence for association and this strengthened when the affected phenotype included bipolar disorder suggesting that genes may not always associate with operationalised diagnostic entities. Several further large Genome Wide Association (GWA) studies on schizophrenia are under way and identified and replicated further loci in well-powered cohorts. The last 2 years have also witnessed an explosion of interest in human Copy Number Variants (CNVs). Deletions recently identified in schizophrenia (1q21.1; 2p16.3; 15q11.2; 15q13.3) have also been most recently found in further neurodevelopmental diseases. Thus, a significant fraction of individuals with neurodevelopmental diseases including schizophrenia carry CNVs and many will be defined as “genomic disorders” in the coming years. These findings could represent a decisive step towards understanding the causes of this severe mental disorder as well as developing new potential treatments. There is new hope that these new avenues will help understanding the neurobiology of schizophrenia in more depth leading to the development of new innovative diagnostic tools and therapies as was the case after the discovery of rare APP and presenilin 1 and 2 mutations in Alzheimer's disease.

Type
Editorials
Copyright
Copyright © Cambridge University Press 2009

References

Abrahams, B.S. & Geschwind, D.H. (2008). Advances in autism genetics: on the threshold of a new neurobiology. Nature Review. Genetics 9, 341355.Google Scholar
Blouin, J.L., Dombroski, B.A., Nath, S.K., Lasseter, V.K., Wolyniec, P.S., Nestadt, G., Thornquist, M., Ullrich, G., McGrath, J., Kasch, L., Lamacz, M., Thomas, M.G., Gehrig, C., Radhakrishna, U., Snyder, S.E., Balk, K.G., Neufeld, K., Swartz, K.L., DeMarchi, N., Papadimitriou, G.N., Dikeos, D.G., Stefanis, C.N., Chakravarti, A., Childs, B., Housman, D.E., Kazazian, H.H., Antonarakis, S. & Pulver, A.E. (1998). Schizophrenia susceptibility loci on chromosomes 13q32 and 8p21. Nature Genetics 20, 7073.CrossRefGoogle ScholarPubMed
Brunetti-Pierri, N., Berg, J.S., Scaglia, F., Belmont, J., Bacino, C.A., Sahoo, T., Lalani, S.R., Graham, B., Lee, B., Shinawi, M., Shen, J., Kang, S.H., Pursley, A., Lotze, T., Kennedy, G., Lansky-Shafer, S., Weaver, C., Roeder, E.R., Grebe, T.A., Arnold, G.L., Hutchison, T., Reimschisel, T., Amato, S., Geragthy, M.T., Innis, J.W., Obersztyn, E., Nowakowska, B., Rosengren, S.S., Bader, P.I., Grange, D.K., Naqvi, S., Garnica, A.D., Bernes, S.M., Fong, C.T., Summers, A., Walters, W.D., Lupski, J.R., Stankiewicz, P., Cheung, S.W. & Patel, A. (2008). Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities. Nature Genetics Epub 2008 Nov.Google Scholar
Brzustowicz, L.M., Hodgkinson, K.A., Chow, E.W., Honer, W.G. & Bassett, A.S. (2000). Location of a major susceptibility locus for familial schizophrenia on chromosome 1q21-q22. Science 288(5466), 678682.CrossRefGoogle Scholar
Cook, E.H. Jr. & Scherer, S.W. (2008). Copy-number variations associated with neuropsychiatric conditions. Nature 455(7215), 919923.CrossRefGoogle ScholarPubMed
de Vries, B.B., Pfundt, R., Leisink, M., Koolen, D.A., Vissers, L.E., Janssen, I.M., Reijmersdal, S., Nillesen, W.M., Huys, E.H., Leeuw, N., Smeets, D., Sistermans, E.A., Feuth, T., Ravenswaaij-Arts, C.M., van Kessel, A.G., Schoenmakers, E.F., Brunner, H.G. & Veltman, J.A. (2005). Diagnostic genome profiling in mental retardation. American Journal of Human Genetics 77, 606616.CrossRefGoogle ScholarPubMed
Detera-Wadleigh, S.D., Goldin, L.R., Sherrington, R., Encio, I., de Miguel, C., Berrettini, W., Gurling, H. & Gershon, E.S. (1989). Exclusion of linkage to 5q11–13 in families with schizophrenia and other psychiatric disorders. Nature 340(6232), 391393.CrossRefGoogle ScholarPubMed
Faraone, S.V., Matise, T., Svrakic, D., Pepple, J., Malaspina, D., Suarez, B., Hampe, C., Zambuto, C.T., Schmitt, K., Meyer, J., Markel, P., Lee, H., Harkavy, Friedman J., Kaufmann, C., Cloninger, C.R. & Tsuang, M.T. (1998). Genome scan of European-American schizophrenia pedigrees: results of the NIMH Genetics Initiative and Millennium Consortium. American Journal of Medical Genetics 10, 81, 290295.Google Scholar
Gill, M., Vallada, H., Collier, D., Sham, P., Holmans, P., Murray, R., McGuffin, P., Nanko, S., Owen, M., Antonarakis, S., Housman, D., Kazazian, H., Nestadt, G., Pulver, A.E., Straub, R.E., MacLean, C.J., Walsh, D., Kendler, K.S., DeLisi, L., Polymeropoulos, M., Coon, H., Byerley, W., Lofthouse, R., Gershon, E., Read, C.M. et al. (1996). A combined analysis of D22S278 marker alleles in affected sib-pairs: support for a susceptibility locus for schizophrenia at chromosome 22q12. Schizophrenia Collaborative Linkage Group (Chromosome 22). American Journal of Medical Genetics 16, 67, 4045.3.0.CO;2-W>CrossRefGoogle ScholarPubMed
International Schizophrenia Consortium (2008). Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature. 455(7210), 237241.Google Scholar
Kirov, G., Gumus, D., Chen, W., Norton, N., Georgieva, L., Sari, M., O'Donovan, M.C., Erdogan, F., Owen, M.J., Ropers, H.H. & Ullmann, R. (2008). Comparative genome hybridization suggests a role for NRXN1 and APBA2 in schizophrenia. Human Molecular Genetics 17, 458465.Google Scholar
Levinson, D.F., Holmans, P., Straub, R.E., Owen, M.J., Wildenauer, D.B., Gejman, P.V., Pulver, A.E., Laurent, C., Kendler, K.S., Walsh, D., Norton, N., Williams, N.M., Schwab, S.G., Lerer, B., Mowry, B.J., Sanders, A.R., Antonarakis, S.E., Blouin, J.L., DeLeuze, J.F. & Mallet, J. (2000). Multicenter linkage study of schizophrenia candidate regions on chromosomes 5q, 6q, 10p, and 13q: schizophrenia linkage collaborative group III. American Journal of Medical Genetics 67, 652663.Google Scholar
Lewis, C.M., Levinson, D.F., Wise, L.H., DeLisi, L.E., Straub, R.E., Hovatta, I., Williams, N.M., Schwab, S.G., Pulver, A.E., Faraone, S.V., Brzustowicz, L.M., Kaufmann, C.A., Garver, D.L., Gurling, H.M., Lindholm, E., Coon, H., Moises, H.W., Byerley, W., Shaw, S.H., Mesen, A., Sherrington, R., O'Neill, F.A., Walsh, D., Kendler, K.S., Ekelund, J., Paunio, T., Lonnqvist, J., Peltonen, L., O'Donovan, M.C., Owen, M.J., Wildenauer, D.B., Maier, W., Nestadt, G., Blouin, J.L., Antonarakis, S.E., Mowry, B.J., Silverman, J.M., Crowe, R.R., Cloninger, C.R., Tsuang, M.T., Malaspina, D., Harkavy-Friedman, J.M., Svrakic, D.M., Bassett, A.S., Holcomb, J., Kalsi, G., McQuillin, A., Brynjolfson, J., Sigmundsson, T., Petursson, H., Jazin, E., Zoega, T. & Helgason, T. (2003). Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia. American Journal of Medical Genetics 73, 3448.Google Scholar
Lin, M.W., Curtis, D., Williams, N., Arranz, M., Nanko, S., Collier, D., McGuffin, P., Murray, R., Owen, M., Gill, M., et al. (1995). Suggestive evidence for linkage of schizophrenia to markers on chromosome 13q14.1-q32. Psychiatric Genetics 5(3), 117–26. Erratum in: Psychiatric Genetics 1996 Spring 6(1), 37.CrossRefGoogle ScholarPubMed
Maier, W., Hofgen, B., Zobel, A. & Rietschel, M. (2005). Genetic models of schizophrenia and bipolar disorder: overlapping inheritance or discrete genotypes? European Archives of Psychiatry and Clinical Neuroscience 255, 159166.Google Scholar
McGuffin, P. & Owen, M.J. (1996). Molecular genetic studies of schizophrenia. Cold Spring Harbor Symposia on Quantitative Biology 61, 815822.Google ScholarPubMed
Mefford, H.C., Sharp, A.J., Baker, C., Itsara, A., Jiang, Z., Buysse, K., Huang, S., Maloney, V.K., Crolla, J.A., Baralle, D., Collins, A., Mercer, C., Norga, K., de Ravel, T., Devriendt, K., Bongers, E.M., de Leeuw, N., Reardon, W., Gimelli, S., Bena, F., Hennekam, R.C., Male, A., Gaunt, L., Clayton-Smith, J., Simonic, I., Park, S.M., Mehta, S.G., Nik-Zainal, S., Woods, C.G., Firth, H.V., Parkin, G., Fichera, M., Reitano, S., Lo, G.M., Li, K.E., Casuga, I., Broomer, A., Conrad, B., Schwerzmann, M., Raber, L., Gallati, S., Striano, P., Coppola, A., Tolmie, J.L., Tobias, E.S., Lilley, C., Armengol, L., Spysschaert, Y., Verloo, P., De Coene, A., Goossens, L., Mortier, G., Speleman, F., van Binsbergen, E., Nelen, M.R., Hochstenbach, R., Poot, M., Gallagher, L., Gill, M., McClellan, J., King, M.C., Regan, R., Skinner, C., Stevenson, R.E., Antonarakis, S.E., Chen, C., Estivill, X., Menten, B., Gimelli, G., Gribble, S., Schwartz, S., Sutcliffe, J.S., Walsh, T., Knight, S.J., Sebat, J., Romano, C., Schwartz, C.E., Veltman, J.A., de Vries, B.B., Vermeesch, J.R., Barber, J.C., Willatt, L., Tassabehji, M. & Eichler, E.E. (2008). Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. New England Journal of Medicine 359, 16851699.Google Scholar
Murthy, S.K., Nygren, A.O., El, Shakankiry H.M., Schouten, J.P., Al, Khayat A.I., Ridha, A. & Al, Ali M.T. (2007). Detection of a novel familial deletion of four genes between BP1 and BP2 of the Prader-Willi/Angelman syndrome critical region by oligo-array CGH in a child with neurological disorder and speech impairment. Cytogenetic and Genome Research 116, 135140.CrossRefGoogle Scholar
Norton, N., Williams, H.J. & Owen, M.J. (2006). An update on the genetics of schizophrenia. Current Opinion in Psychiatry 19, 158164.Google Scholar
O'Donovan, M.C., Kirov, G. & Owen, M.J. (2008a). Phenotypic variations on the theme of CNVs. Nature Genetics 40, 13921393.CrossRefGoogle ScholarPubMed
O'Donovan, M.C., Craddock, N., Norton, N., Williams, H., Peirce, T., Moskvina, V., Nikolov, I., Hamshere, M., Carroll, L., Georgieva, L., Dwyer, S., Holmans, P., Marchini, J.L., Spencer, C.C., Howie, B., Leung, H.T., Hartmann, A.M., M�r, H.J., Morris, D.W., Shi, Y., Feng, G., Hoffmann, P., Propping, P., Vasilescu, C., Maier, W., Rietschel, M., Zammit, S., Schumacher, J., Quinn, E.M., Schulze, T.G., Williams, N.M., Giegling, I., Iwata, N., Ikeda, M., Darvasi, A., Shifman, S., He, L., Duan, J., Sanders, A.R., Levinson, D.F., Gejman, P.V., Cichon, S., N�n, M.M., Gill, M., Corvin, A., Rujescu, D., Kirov, G., Owen, M.J., Buccola, N.G., Mowry, B.J., Freedman, R., Amin, F., Black, D.W., Silverman, J.M., Byerley, W.F., Cloninger, C.R. & Molecular Genetics of Schizophrenia Collaboration (2008b). Identification of loci associated with schizophrenia by genome-wide association and follow-up. Nature Genetics 40, 10531055.Google Scholar
Owen, M.J. (2005). Genomic approaches to schizophrenia. Clinical Therapy 27, Suppl. A, S27.Google Scholar
Owen, M.J., Craddock, N. & Jablensky, A. (2007). The genetic deconstruction of psychosis. Schizophrenia Bulletin 33, 905911.Google Scholar
Ramocki, M.B. & Zoghbi, H.Y. (2008). Failure of neuronal homeostasis results in common neuropsychiatric phenotypes. Nature 455(7215), 912918.CrossRefGoogle ScholarPubMed
Rujescu, D., Ingason, A., Cichon, S., Pietilainen, O.P., Barnes, M.R., 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, P.I., Hardarsson, G., Jonsdottir, G.A., Gustafsson, O., Fossdal, R., Giegling, I., Moller, H.J., Hartmann, A., Hoffmann, P., Crombie, C., Fraser, G., Walker, N., Lonnqvist, J., Suvisaari, J., Tuulio-Henriksson, A., Andreassen, O.A., Djurovic, S., Hansen, T., Werge, T., Melle, I., Kiemeney, L.A., Franke, B., Buizer-Voskamp, J.E., Ophoff, R.A., Rietschel, M., Nothen, M.M., Stefansson, K., Peltonen, L., StClair, D., Stefansson, H. & Collier, D.A. (2008). Disruption of the neurexin 1 gene is associated with schizophrenia. Human Molecular Genetics, Epub 2008 Oct.Google Scholar
Sanders, A.R., Duan, J., Levinson, D.F., Shi, J., He, D., Hou, C., Burrell, G.J., Rice, J.P., Nertney, D.A., Olincy, A., Rozic, P., Vinogradov, S., Buccola, N.G., Mowry, B.J., Freedman, R., Amin, F., Black, D.W., Silverman, J.M., Byerley, W.F., Crowe, R.R., Cloninger, C.R., Martinez, M. & Gejman, P.V. (2008). No significant association of 14 candidate genes with schizophrenia in a large European ancestry sample: implications for psychiatric genetics. American Journal of Psychiatry 165, 497506. Erratum in: American Journal of Psychiatry 165, 1359.Google Scholar
Schizophrenia linkage collaborative group (1996). Additional support for schizophrenia linkage on chromosomes 6 and 8: a multicenter study. Schizophrenia Linkage Collaborative Group for Chromosomes 3, 6 and 8. American Journal of Medical Genetics 22; 67, 580594.Google Scholar
Schwab, S.G., Eckstein, G.N., Hallmayer, J., Lerer, B., Albus, M., Borrmann, M., Lichtermann, D., Ertl, M.A., Maier, W. & Wildenauer, D.B. (1997). Evidence suggestive of a locus on chromosome 5q31 contributing to susceptibility for schizophrenia in German and Israeli families by multipoint affected sib-pair linkage analysis. Molecular Psychiatry 2, 156160.Google Scholar
Schwab, S.G., Knapp, M., Mondabon, S., Hallmayer, J., Borrmann-Hassenbach, M., Albus, M., Lerer, B., Rietschel, M., Trixler, M., Maier, W. & Wildenauer, D.B. (2003). Support for association of schizophrenia with genetic variation in the 6p22.3 gene, dysbindin, in sib-pair families with linkage and in an additional sample of triad families. American Journal of Human Genetics 72, 185190.Google Scholar
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, Y.H., Hicks, J., Spence, S.J., Lee, A.T., Puura, K., Lehtimaki, T., Ledbetter, D., Gregersen, P.K., Bregman, J., Sutcliffe, J.S., Jobanputra, V., Chung, W., Warburton, D., King, M.C., Skuse, D., Geschwind, D.H., Gilliam, T.C., Ye, K. & Wigler, M. (2007). Strong association of de novo copy number mutations with autism. Science 316(5823), 445449.Google Scholar
Sharp, A.J., Hansen, S., Selzer, R.R., Cheng, Z., Regan, R., Hurst, J.A., Stewart, H., Price, S.M., Blair, E., Hennekam, R.C., Fitzpatrick, C.A., Segraves, R., Richmond, T.A., Guiver, C., Albertson, D.G., Pinkel, D., Eis, P.S., Schwartz, S., Knight, S.J. & Eichler, E.E. (2006). Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome. Nature Genetics 38,10381042.CrossRefGoogle ScholarPubMed
Sharp, A.J., Mefford, H.C., Li, K., Baker, C., Skinner, C., Stevenson, R.E., Schroer, R.J., Novara, F., De Gregori, M., Ciccone, R., Broomer, A., Casuga, I., Wang, Y., Xiao, C., Barbacioru, C., Gimelli, G., Bernardina, B.D., Torniero, C., Giorda, R., Regan, R., Murday, V., Mansour, S., Fichera, M., Castiglia, L., Failla, P., Ventura, M., Jiang, Z., Cooper, G.M., Knight, S.J., Romano, C., Zuffardi, O., Chen, C., Schwartz, C.E. & Eichler, E.E. (2008). A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures. Nature Genetics 40, 322328.Google Scholar
Sherrington, P.D., Nacheva, E., Fischer, P., Rees, J.K., Hoyle, C., Dyer, M., Harper, P., Knight, C. & Hayhoe, F.G. (1988). Translocation 5;21 and interstitial deletion of chromosome 7 in a case of chronic myelomonocytic leukemia. Cancer Genetics and Cytogenetics 31, 247252.CrossRefGoogle Scholar
Slavotinek, A.M. (2008). Novel microdeletion syndromes detected by chromosome microarrays. Human Genetics 124, 117.Google Scholar
StClair, D. (2008). Copy number variation and schizophrenia. Schizophrenia Bulletin Epub 2008 Nov.Google Scholar
Stefansson, H., Rujescu, D., Cichon, S., Pietilainen, O.P., Ingason, A., Steinberg, S., Fossdal, R., Sigurdsson, E., Sigmundsson, T., Buizer-Voskamp, J.E., Hansen, T., Jakobsen, K.D., Muglia, P., Francks, C., Matthews, P.M., Gylfason, A., Halldorsson, B.V., Gudbjartsson, D., Thorgeirsson, T.E., Sigurdsson, A., Jonasdottir, A., Jonasdottir, A., Bjornsson, A., Mattiasdottir, S., Blondal, T., Haraldsson, M., Magnusdottir, B.B., Giegling, I., Moller, H.J., Hartmann, A., Shianna, K.V., Ge, D., Need, A.C., 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, T.W., Wang, A.G., Ullum, H., Djurovic, S., Melle, I., Olesen, J., Kiemeney, L.A., Franke, B., Sabatti, C., Freimer, N.B., Gulcher, J.R., Thorsteinsdottir, U., Kong, A., Andreassen, O.A., Ophoff, R.A., Georgi, A., Rietschel, M., Werge, T., Petursson, H., Goldstein, D.B., Nothen, M.M., Peltonen, L., Collier, D.A., StClair, D. & Stefansson, K. (2008). Large recurrent microdeletions associated with schizophrenia. Nature 455(7210), 232236.CrossRefGoogle ScholarPubMed
Straub, R.E., MacLean, C.J., O'Neill, F.A., Walsh, D. & Kendler, K.S. (1997). Support for a possible schizophrenia vulnerability locus in region 5q22–31 in Irish families. Molecular Psychiatry 2, 148155.Google Scholar
Straub, R.E., MacLean, C.J., Martin, R.B., Ma, Y., Myakishev, M.V., Harris-Kerr, C., Webb, B.T., O'Neill, F.A., Walsh, D. & Kendler, K.S. (1998). A schizophrenia locus may be located in region 10p15-p11. American Journal of Medical Genetics 81, 296301.Google Scholar
Straub, R.E., Jiang, Y., MacLean, C.J., Ma, Y., Webb, B.T., Myakishev, M.V., Harris-Kerr, C., Wormley, B., Sadek, H., Kadambi, B., Cesare, A.J., Gibberman, A., Wang, X., O'Neill, F.A., Walsh, D. & Kendler, K.S. (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, 337348.CrossRefGoogle ScholarPubMed
Walsh, T., McClellan, J.M., McCarthy, S.E., Addington, A.M., Pierce, S.B., Cooper, G.M., Nord, A.S., Kusenda, M., Malhotra, D., Bhandari, A., Stray, S.M., Rippey, C.F., Roccanova, P., Makarov, V., Lakshmi, B., Findling, R.L., 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, E.E., Meltzer, P.S., Nelson, S.F., Singleton, A.B., Lee, M.K., Rapoport, J.L., King, M.C. & Sebat, J. (2008). Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 320(5875), 539543.CrossRefGoogle ScholarPubMed
Weinberger, D.R. (2005). Genetic mechanisms of psychosis: in vivo and postmortem genomics. Clinical Therapy 27, Suppl A, S815.Google Scholar
Weiss, L.A., Shen, Y., Korn, J.M., Arking, D.E., Miller, D.T., Fossdal, R., Saemundsen, E., Stefansson, H., Ferreira, M.A., Green, T., Platt, O.S., Ruderfer, D.M., Walsh, C.A., Altshuler, D., Chakravarti, A., Tanzi, R.E., Stefansson, K., Santangelo, S.L., Gusella, J.F., Sklar, P., Wu, B.L. & Daly, M.J. (2008). Association between microdeletion and microduplication at 16p11.2 and autism. New England Journal of Medicine 358, 667675.Google Scholar