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Linkage and association studies of schizophrenia

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Abstract

Recent twin studies confirm that schizophrenia is highly heritable, but attempts to locate and identify genes have proved to be difficult. This is largely because major genes appear to be rare or nonexistent. Instead, genetic liability almost certainly results from the combined effects of multiple susceptibility loci and most studies have been underequipped to detect such effects. Nevertheless, several regions of the genome have been implicated by more than one linkage study and chromosome 22q has been implicated by linkage and by studies of patients with microdeletions. Recent work attempting to refine regions of interest using linkage dysequilibrium mapping has identified four promising and novel “positional candidates;” they are neuregulin-1 on chromosome 8p-p21, G72 located at chromosome 13q34, dysbindin at 6p22.3, and proline dehydrogenase, which is a gene that maps to chromosome 22q11. In addition, there is renewed interest in a fifth gene, catechol-O-methyltransferase, also on chromosome 22q11.

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References and Recommended Reading

  1. Cardno AG, Gottesman II: Twin studies of schizophrenia: from bow-and-arrow concordances to Star Wars Mx and functional genomics. Am J Med Genet 2000, 97:12–17.

    Article  PubMed  CAS  Google Scholar 

  2. Farmer AE, McGuffin P, Gottesman II: Twin concordance for DSM-III schizophrenia.: scrutinizing the validity of the definition. Arch Gen Psychiatry 1987, 44:634–641.

    PubMed  CAS  Google Scholar 

  3. McGuffin P, Sturt E: Genetic markers in schizophrenia. Hum Hered 1986, 36:65–88.

    Article  PubMed  CAS  Google Scholar 

  4. The International Human Genome Mapping Consortium: Initial sequencing and analysis of the human genome. Nature 2000, 409:860–921.

    Google Scholar 

  5. Sham P, McGuffin P: Linkage and association. In Psychiatric Genetics and Genomics. Edited by McGuffin P, Owen MJ, Gottesman II. Oxford: Oxford University Press; 2002:55–73.

    Google Scholar 

  6. Liddell MB, Williams J, Owen MJ: The dementias. In Psychiatric Genetics and Genomics. Edited by McGuffin P, Owen MJ, Gottesman II. Oxford: Oxford University Press; 2002:341–396.

    Google Scholar 

  7. Thomson G: Significance levels in genome scans. Adv Genet 2001, 42:475–486.

    Article  PubMed  CAS  Google Scholar 

  8. Riley BP, McGuffin P: Linkage and associated studies of schizophrenia. Am J Med Genet 2000, 97:23–44.

    Article  PubMed  CAS  Google Scholar 

  9. Lander E, Kruglyak L: Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 1995, 11:241–247.

    Article  PubMed  CAS  Google Scholar 

  10. Brzustowicz LM, Hodgkinson KA, Chow EW, et al.: Location of a major susceptibility locus for familial schizophrenia on chromosome 1q21-q22. Science 2000, 288:678–682.

    Article  PubMed  CAS  Google Scholar 

  11. Gurling HM, Kalsi G, Brynjolfson J, et al.: Genomewide genetic linkage analysis confirms the presence of susceptibility loci for schizophrenia, on chromosomes 1q32.2, 5q33.2, and 8p21-22 and provides support for linkage to schizophrenia, on chromosomes 11q23.3-24 and 20q12.1-11.23. Am J Hum Genet 2001, 68:661–673.

    Article  PubMed  CAS  Google Scholar 

  12. Levinson DF, Holmans PA, Laurent C, et al.: No major schizophrenia locus detected on chromosome 1q in a large multicenter sample. Science 2002, 296:739–741.

    Article  PubMed  CAS  Google Scholar 

  13. Blackwood DH, Visscher PM, Muir WJ: Genetic studies of bipolar affective disorder in large families. Br J Psychiatry 2001, 41:134–136.

    Article  Google Scholar 

  14. Hovatta I, Varilo T, Suvisaari J, et al.: A genomewide screen for schizophrenia genes in an isolated Finnish subpopulation, suggesting multiple susceptibility loci. Am J Hum Genet 1999, 65:1114–1124.

    Article  PubMed  CAS  Google Scholar 

  15. Ekelund J, Lichtermann D, Hovatta I, et al.: Genome-wide scan for schizophrenia in the Finnish population: evidence for a locus on chromosome 7q22. Hum Mol Genet 2000, 9:1049–1057.

    Article  PubMed  CAS  Google Scholar 

  16. Owen MJ, O’Donovan MC, Gottesman II: Schizophrenia. In Psychiatric Genetics and Genomics. Edited by McGuffin P, Owen MJ, Gottesman II. Oxford: Oxford University Press; 2002:247–266.

    Google Scholar 

  17. Murphy KC, Jones LA, Owen MJ: High rates of schizophrenia in adults with velo-cardio-facial syndrome. Arch Gen Psychiatry 1999, 56:940–945.

    Article  PubMed  CAS  Google Scholar 

  18. Badner JA, Gershon ES: Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia. Mol Psychiatry 2002, 7:405–411.

    Article  PubMed  CAS  Google Scholar 

  19. Suarez BK, Hamper CL, Van Eeerdewegh P: Problems of replivating linkage claims in psychiatry. In Genetic Approaches to Mental Disorders. Edited by Gershon ES, Cloninger CR. Washington DC; American Psychiatric Press: 1994.

    Google Scholar 

  20. Baron M: Genetics of schizophrenia and the new millennium: progress and pitfalls. Am J Hum Genet 2001, 68:299–312.

    Article  PubMed  CAS  Google Scholar 

  21. Polesskaya OO, Sokolov BP: Differential expression of the "C" and "T" alleles of the 5-HT2A receptor gene in the temporal cortex of normal individuals and schizophrenics. J Neurosci Res 2002, 67:812–822.

    Article  PubMed  CAS  Google Scholar 

  22. Williams J, McGuffin P, Nothen M, Owen MJ: Meta-analysis of association between the 5-HT2a receptor T102C polymorphism and schizophrenia. EMASS Collaborative Group. European Multicentre Association Study of Schizophrenia. Lancet 1997, 349:1221.

    Article  PubMed  CAS  Google Scholar 

  23. Chen RY, Sham P, Chen EY, et al.: No association between T102C polymorphism of serotonin-2A receptor gene and clinical phenotypes of Chinese schizophrenic patients. Psychiatry Res 2001, 105:175–185.

    Article  PubMed  CAS  Google Scholar 

  24. Haider MZ, Zahid MA: No evidence for an association between the 5-hydroxytryptamine 5-HT2a receptor gene and schizophrenia in Kuwaiti Arabs. Psychiatry Clin Neurosci 2002, 56:465–467.

    Article  PubMed  CAS  Google Scholar 

  25. Williams J, Spurlock G, Holmans P, et al.: A meta-analysis and transmission dysequilibrium study of association between the dopamine D3 receptor gene and schizophrenia. Mol Psychiatry 1998, 3:141–149.

    Article  PubMed  CAS  Google Scholar 

  26. Anney RJ, Rees MI, Bryan E, et al.: Characterization, mutation detection, and association analysis of alternative promoters and 5′ UTRs of the human dopamine D3 receptor gene in schizophrenia. Mol Psychiatry 2002, 7:493–502.

    Article  PubMed  CAS  Google Scholar 

  27. Williams NM, Bowen T, Spurlock G, et al.: Determination of the genomic structure and mutation screening in schizophrenic individuals for five subunits of the N-methyl-Daspartate glutamate receptor. Mol Psychiatry 2002, 7:508–514.

    Article  PubMed  CAS  Google Scholar 

  28. Begni S, Popoli M, Moraschi S, et al.: Association between the ionotropic glutamate receptor kainate 3 (GRIK3) ser310ala polymorphism and schizophrenia. Mol Psychiatry 2002, 7:416–418.

    Article  PubMed  CAS  Google Scholar 

  29. Devon RS, Anderson S, Teague PW, et al.: The genomic organization of the metabotropic glutamate receptor subtype 5 gene, and its association with schizophrenia. Mol Psychiatry 2001, 6:311–314.

    Article  PubMed  CAS  Google Scholar 

  30. Wei J, Hemmings GP: The NOTCH4 locus is associated with susceptibility to schizophrenia. Nat Genet 2000, 25:376–377.

    Article  PubMed  CAS  Google Scholar 

  31. Ujike H, Yamamoto A, Tanaka Y, et al.: Association study of CAG repeats in the KCNN3 gene in Japanese patients with schizophrenia, schizoaffective disorder and bipolar disorder. Psychiatry Res 2001, 101:203–207.

    Article  PubMed  CAS  Google Scholar 

  32. Sklar P, Schwab SG, Williams NM, et al.: Association analysis of NOTCH4 loci in schizophrenia using family and population-based controls. Nat Genet 2001, 28:126–128.

    Article  PubMed  CAS  Google Scholar 

  33. Fan JB, Tang JX, Gu NF, et al.: A family-based and case-control association study of the NOTCH4 gene and schizophrenia. Mol Psychiatry 2002, 7:100–103.

    Article  PubMed  CAS  Google Scholar 

  34. Stefansson H, Sigurdsson E, Steinthorsdottir V, et al.: Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet 2002, 71:877–892. This study identifies a promising positional candidate in a linkage region in an ethnically homogenous population.

    Article  PubMed  Google Scholar 

  35. Stefansson H, Sarginson J, Kong A, et al.: Association of neuregulin-1 with schizophrenia confirmed in a Scottish population. Am J Hum Genet 2003, 72:83–87.

    Article  PubMed  CAS  Google Scholar 

  36. Chumakov I, Blumenfeld M, Guerassimenko O, et al.: Genetic and physiological data implicating the new human gene G72 and the gene for D-amino acid oxidase in schizophrenia. Proc Natl Acad Sci U S A 2002, 99:13675–13680. Identification of a new gene that appears to be associated with a small but significant increase in risk of schizophrenia and which interacts with D-amino acid oxidase, modulating glutamatergic transmission.

    Article  PubMed  CAS  Google Scholar 

  37. Straub RE, Jiang Y, MacLean CJ, et al.: Genetic variation in the 6p22.3 gene DTNBP1, the human ortholog of the mouse dysbindin gene, is associated with schizophrenia. Am J Hum Genet 2002, 71:337–348. This study attempts to narrow down the region of interest on chromosome 6p, and presents evidence of an association with a SNP haplotype in the dysbindin gene.

    Article  PubMed  CAS  Google Scholar 

  38. Liu H, Heath SC, Sobin C, et al.: Genetic variation at the 22q11 PRODH2/DGCR6 locus presents an unusual pattern and increases susceptibility to schizophrenia. Proc Natl Acad Sci U S A 2002, 99:3717–3722.

    Article  PubMed  CAS  Google Scholar 

  39. Jacquet H, Raux G, Thibaut F, et al.: PRODH mutations and hyperprolinemia in a subset of schizophrenic patients. Hum Mol Genet 2002, 11:2243–2249. This paper and Liu et al. [37] independently implicate the proline dehydrogenase gene in schizophrenia with hypoactivity increasing susceptibility to the disorder.

    Article  PubMed  CAS  Google Scholar 

  40. Lachman HM, Papolos DF, Saito T, et al.: Human catechol-Omethyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics 1996, 6:243–250.

    Article  PubMed  CAS  Google Scholar 

  41. Li T, Sham PC, Vallada H, Xie T: Preferential transmission of the high activity allele of COMT in schizophrenia. Psychiatr Genet 1996, 6:131–133.

    Article  PubMed  CAS  Google Scholar 

  42. Kunugi H, Vallada HP, Sham PC, et al.: Catechol-O-methyltransferase polymorphisms and schizophrenia: a transmission disequilibrium study in multiply affected families. Psychiatr Genet 1997, 7:97–101.

    Article  PubMed  CAS  Google Scholar 

  43. Egan MF, Goldberg TE, Kolachana BS, et al.: Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci U S A 2001, 98:6917–6922. This study found evidence that the COMT val allele, which increases prefrontal dopamine catabolism, impairs prefrontal cognition and physiology. The authors suggest that this mechanism slightly increases the risk for schizophrenia.

    Article  PubMed  CAS  Google Scholar 

  44. Daniels JK, Williams NM, Williams J, et al.: No evidence for allelic association between schizophrenia and a polymorphism determining high or low catechol-O-methyltransferase activity. Am J Psychiatry 1996, 153:268–270.

    PubMed  CAS  Google Scholar 

  45. Chen EY, Lam LC, Chen RY, et al.: Neuropsychological correlates of sustained attention in schizophrenia. Schizophr Res 1997, 24:299–310.

    Article  PubMed  CAS  Google Scholar 

  46. Strous RD, Bark N, Woerner M, Lachman HM: Lack of association of a functional catechol-O-methyltransferase gene polymorphism in schizophrenia. Biol Psychiatry 1997, 41:493–495.

    Article  PubMed  CAS  Google Scholar 

  47. Norton N, Kirov G, Zammit S, et al.: Schizophrenia and functional polymorphisms in the MAOA and COMT genes: no evidence for association or epistasis. Am J Med Genet 2002, 114:491–496.

    Article  PubMed  Google Scholar 

  48. Ohmori O, Shinkai T, Kojima H, et al.: Association study of a functional catechol-O-methyltransferase gene polymorphism in Japanese schizophrenics. Neurosci Lett 1998, 243:109–112.

    Article  PubMed  CAS  Google Scholar 

  49. Shifman S, Bronstein M, Sternfeld M, et al.: A highly significant association between a COMT haplotype and schizophrenia. Am J Hum Genet 2002, 71:1296–1302. The most impressive results among studies of positional candidates suggest a relationship between schizophrenia and a different COMT variant from that studied by previous authors.

    Article  PubMed  CAS  Google Scholar 

  50. Moises HW, Zoega T, Gottesman II: The glial growth factors deficiency and synaptic destabilization hypothesis of schizophrenia. BMC Psychiatry 2002, 2:8. A provocative and speculative hypothesis piece that attempt to put forward to coherent set of mechanisms by which genes on linkage regions may exert their effects.

    Article  PubMed  Google Scholar 

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  1. SGDP Research Centre, Institute of Psychiatry, King’s College London, De Crespigny Park, SE5 8AF, London, UK

    Peter McGuffin MD

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  1. Peter McGuffin MD
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  2. Kopal Tandon MD
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  3. Alejandro Corsico MD
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McGuffin, P., Tandon, K. & Corsico, A. Linkage and association studies of schizophrenia. Curr Psychiatry Rep 5, 121–127 (2003). https://doi.org/10.1007/s11920-003-0028-y

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