1 The Pharmacogenomics Journal 2005 Vol: 5(2):81-88. DOI: 10.1038/sj.tpj.6500293

Cytogenetics and gene discovery in psychiatric disorders

The disruption of genes by balanced translocations and other rare germline chromosomal abnormalities has played an important part in the discovery of many common Mendelian disorder genes, somatic oncogenes and tumour supressors. A search of published literature has identified 15 genes whose genomic sequences are directly disrupted by translocation breakpoints in individuals with neuropsychiatric illness. In these cases, it is reasonable to hypothesise that haploinsufficiency is a major factor contributing to illness. These findings suggest that the predicted polygenic nature of psychiatric illness may not represent the complete picture; genes of large individual effect appear to exist. Cytogenetic events may provide important insights into neurochemical pathways and cellular processes critical for the development of complex psychiatric phenotypes in the population at large.

Mentions
Altmetric
References
  1. Berrettini WH. Genetics of psychiatric disease. Annu Rev Med 2000; 51: 465−479 , .
    • . . . Twin and family studies have made it abundantly clear that powerful genetic risk factors act in concert with environmental factors to give rise to psychiatric illnesses such as schizophrenia, bipolar affective disorder and unipolar depression.1 However, the precise nature of this contribution is not well understood . . .
  2. Neale BM & Sham PC. The future of association studies: gene-based analysis and replication. Am J Hum Genet 2004; 75: 353−362 , .
  3. O'Donovan MC, Williams NM & Owen MJ. Recent advances in the genetics of schizophrenia. Hum Mol Genet 2003; 12: 125−133 , .
    • . . . These include neuregulin (NRG1), dysbindin (DTNBP1), G72, COMT and RGS4 (recently reviewed in O'Donovan et al3 and Harrison and Weinberger4) . . .
  4. Harrison PJ & Weinberger DR. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 2005; 10: 40−68 , .
    • . . . These include neuregulin (NRG1), dysbindin (DTNBP1), G72, COMT and RGS4 (recently reviewed in O'Donovan et al3 and Harrison and Weinberger4) . . .
  5. Mukai J, Liu H, Burt RA, Swor DE, Lai WS & Karayiorgou M et al.. Evidence that the gene encoding ZDHHC8 contributes to the risk of schizophrenia. Nat Genet 2004; 36: 725−731 , .
    • . . . In only one instance, the ZDHHC8 gene, has an associated SNP been shown to have a defined effect on gene function.5 In addition, there are marked differences between studies in the details of the associated markers or haplotypes implying allelic heterogeneity at individual gene loci: particularly between different geographical populations, as is the case in simple Mendelian disorders. . . .
  6. Tjio JH & Levan A. The chromosome number in man. Hereditas 1956; 42: 1−6 , .
    • . . . In the last half-century human cytogenetics has emerged as a distinct discipline following the discovery of the number and form of the human chromosomal complement.6, 7, 8 Within the last decade, it has become possible to translate chromosome position into annotated genomic DNA sequence allowing cytogenetics to proceed from an observational science to a diagnostic tool and, more recently, a direct means to isolate disease genes. . . .
  7. Patau K. The identification of individual chromosomes, especially in man. Am J Hum Genet 1960; 12: 250−276 , .
    • . . . In the last half-century human cytogenetics has emerged as a distinct discipline following the discovery of the number and form of the human chromosomal complement.6, 7, 8 Within the last decade, it has become possible to translate chromosome position into annotated genomic DNA sequence allowing cytogenetics to proceed from an observational science to a diagnostic tool and, more recently, a direct means to isolate disease genes. . . .
  8. Trask BJ. Human cytogenetics: 46 chromosomes, 46 years and counting. Nat Rev Genet 2002; 3: 769−778 , .
    • . . . In the last half-century human cytogenetics has emerged as a distinct discipline following the discovery of the number and form of the human chromosomal complement.6, 7, 8 Within the last decade, it has become possible to translate chromosome position into annotated genomic DNA sequence allowing cytogenetics to proceed from an observational science to a diagnostic tool and, more recently, a direct means to isolate disease genes. . . .
  9. International Human Genome Sequencing Consortium. Initial sequencing and analysis of the human genome. Nature 2001; 409: 860−921 , .
    • . . . Assuming an average gene size of 27 kb,9 a genome size of 3 billion bases, two breakpoints per chromosome abnormality (eg a typical reciprocal translocation/inversion) and a frequency of such abnormalities in the population of 0.29–0.56%10, 11 then, providing the disruption is compatible with life, any given gene would be cytogenetically disrupted in 3–6 individuals in the UK population of 60 million . . .
  10. Jacobs PA, Browne C, Gregson N, Joyce C & White H. Estimates of the frequency of chromosome abnormalities detectable in unselected newborns using moderate levels of banding. J Med Genet 1992; 29: 103−108 , .
    • . . . Assuming an average gene size of 27 kb,9 a genome size of 3 billion bases, two breakpoints per chromosome abnormality (eg a typical reciprocal translocation/inversion) and a frequency of such abnormalities in the population of 0.29–0.56%10, 11 then, providing the disruption is compatible with life, any given gene would be cytogenetically disrupted in 3–6 individuals in the UK population of 60 million . . .
  11. Nielsen J & Wohlert M. Chromosome abnormalities found among 34,916 newborn children: results from a 13-year incidence study in Aarhus, Denmark. Hum Genet 1991; 87: 81−83 , .
    • . . . Assuming an average gene size of 27 kb,9 a genome size of 3 billion bases, two breakpoints per chromosome abnormality (eg a typical reciprocal translocation/inversion) and a frequency of such abnormalities in the population of 0.29–0.56%10, 11 then, providing the disruption is compatible with life, any given gene would be cytogenetically disrupted in 3–6 individuals in the UK population of 60 million . . .
  12. Crolla JA & Van Heyningen V. Frequent chromosome aberrations revealed by molecular cytogenetic studies in patients with aniridia. Am J Hum Genet 2002; 71: 1138−1149 , .
    • . . . In a recent study of aniridia, 30 of 77 patients studied were found to have a variety of chromosomal abnormalities including deletions and translocations around the Wilms tumour locus on 11p.12 In addition to the germline chromosome rearrangements described above, somatic rearrangements in tumours and leukaemias have aided the identification of many new oncogenes and tumour suppressors.13 . . .
  13. Rowley JD. The critical role of chromosome translocations in human leukemias. Annu Rev Genet 1998; 32: 495−519 , .
  14. Kurahashi H & Emanuel BS. Long AT-rich palindromes and the constitutional t(11;22) breakpoint. Hum Mol Genet 2001; 10: 2605−2617 , .
    • . . . These suggest that either particular chromosomal motifs, for example, low copy repeats, or AT-rich palindromes or, alternatively, the physical properties of the DNA sequences increase the risk of architectural rearrangements.14, 15, 16, 17, 18, 19, 20 Different explanations are likely to be required for random (unique) or conserved (recurrent) rearrangements. . . .
  15. Stankiewicz P & Lupski JR. Genome architecture, rearrangements and genomic disorders. Trends Genet 2002; 18: 74−82 , .
    • . . . These suggest that either particular chromosomal motifs, for example, low copy repeats, or AT-rich palindromes or, alternatively, the physical properties of the DNA sequences increase the risk of architectural rearrangements.14, 15, 16, 17, 18, 19, 20 Different explanations are likely to be required for random (unique) or conserved (recurrent) rearrangements. . . .
  16. Bi W, Park SS, Shaw CJ, Withers MA, Patel PI & Lupski JR. Reciprocal crossovers and a positional preference for strand exchange in recombination events resulting in deletion or duplication of chromosome 17p11.2. Am J Hum Genet 2003; 73: 1302−1315 , .
    • . . . These suggest that either particular chromosomal motifs, for example, low copy repeats, or AT-rich palindromes or, alternatively, the physical properties of the DNA sequences increase the risk of architectural rearrangements.14, 15, 16, 17, 18, 19, 20 Different explanations are likely to be required for random (unique) or conserved (recurrent) rearrangements. . . .
  17. Spiteri E, Babcock M, Kashork CD, Wakui K, Gogineni S & Lewis DA et al.. Frequent translocations occur between low copy repeats on chromosome 22q11.2 (LCR22s) and telomeric bands of partner chromosomes. Hum Mol Genet 2003; 12: 1823−1837 , .
    • . . . These suggest that either particular chromosomal motifs, for example, low copy repeats, or AT-rich palindromes or, alternatively, the physical properties of the DNA sequences increase the risk of architectural rearrangements.14, 15, 16, 17, 18, 19, 20 Different explanations are likely to be required for random (unique) or conserved (recurrent) rearrangements. . . .
  18. Barbouti A, Stankiewicz P, Nusbaum C, Cuomo C, Cook A & Hoglund M et al.. The breakpoint region of the most common isochromosome, i(17q), in human neoplasia is characterized by a complex genomic architecture with large, palindromic, low-copy repeats. Am J Hum Genet 2003; 74: 1−10 , .
    • . . . These suggest that either particular chromosomal motifs, for example, low copy repeats, or AT-rich palindromes or, alternatively, the physical properties of the DNA sequences increase the risk of architectural rearrangements.14, 15, 16, 17, 18, 19, 20 Different explanations are likely to be required for random (unique) or conserved (recurrent) rearrangements. . . .
  19. Shaw CJ & Lupski JR. Implications of human genome architecture for rearrangement-based disorders: the genomic basis of disease. Hum Mol Genet 2004; 13: 57−64 , .
    • . . . These suggest that either particular chromosomal motifs, for example, low copy repeats, or AT-rich palindromes or, alternatively, the physical properties of the DNA sequences increase the risk of architectural rearrangements.14, 15, 16, 17, 18, 19, 20 Different explanations are likely to be required for random (unique) or conserved (recurrent) rearrangements. . . .
  20. Gotter AL, Shaikh TH, Budarf ML, Rhodes CH & Emanuel BS. A palindrome-mediated mechanism distinguishes translocations involving LCR-B of chromosome 22q11.2. Hum Mol Genet 2004; 13: 103−115 , .
    • . . . These suggest that either particular chromosomal motifs, for example, low copy repeats, or AT-rich palindromes or, alternatively, the physical properties of the DNA sequences increase the risk of architectural rearrangements.14, 15, 16, 17, 18, 19, 20 Different explanations are likely to be required for random (unique) or conserved (recurrent) rearrangements. . . .
  21. Kleinjan DJ & van Heyningen V. Position effect in human genetic disease. Hum Mol Genet 1998; 7: 1611−1618 , .
    • . . . Many other examples exist of abnormalities where the breakpoint lies outside the coding portion of the bona fide disease gene (by up to 1 Mb in some cases) but still perturbs function through a position effect or the separation of enhancer elements from the promoter.21, 22, 23 However, these instances have required considerable confirmatory experimentation . . .
  22. Sutherland HF, Wadey R, McKie JM, Taylor C, Atif U & Johnstone KA et al.. Identification of a novel transcript disrupted by a balanced translocation associated with DiGeorge syndrome. Am J Hum Genet 1996; 59: 23−31 , .
    • . . . Many other examples exist of abnormalities where the breakpoint lies outside the coding portion of the bona fide disease gene (by up to 1 Mb in some cases) but still perturbs function through a position effect or the separation of enhancer elements from the promoter.21, 22, 23 However, these instances have required considerable confirmatory experimentation . . .
  23. Kleinjan DA, Seawright A, Schedl A, Quinlan RA, Danes S & van Heyningen V. Aniridia-associated translocations, DNase hypersensitivity, sequence comparison and transgenic analysis redefine the functional domain of PAX6. Hum Mol Genet 2001; 10: 2049−2059 , .
    • . . . Many other examples exist of abnormalities where the breakpoint lies outside the coding portion of the bona fide disease gene (by up to 1 Mb in some cases) but still perturbs function through a position effect or the separation of enhancer elements from the promoter.21, 22, 23 However, these instances have required considerable confirmatory experimentation . . .
  24. Gratacos M, Nadal M, Martin-Santos R, Pujana MA, Gago J & Peral B et al.. A polymorphic genomic duplication on human chromosome 15 is a susceptibility factor for panic and phobic disorders. Cell 2001; 106: 367−379 , .
    • . . . For similar reasons, we have not included the contribution of cytogenetics to important neurological associates such as mental retardation (UK equivalent terminology is learning disability), dup15 (associated with joint laxity and panic disorder) or genomic disorders that are associated with clear behavioural phenotypes such as Williams syndrome (overfriendliness and anxiety), Smith–Magenis syndrome (self-injury), Prader–Willi syndrome (hyperphagia) or chromosome 22 deletion syndrome (associated with psychosis).24, 25, 26, 27, 28 Neither shall we discuss the important work being carried out on the phenomenon of subtelomeric deletions associated with idiopathic mental retardation29, 30 as well as autism.31, 32, 33, 34 . . .
  25. Tassabehji M. Williams−Beuren syndrome: a challenge for genotype−phenotype correlations. Hum Mol Genet 2003; 12: 229−237 , .
    • . . . For similar reasons, we have not included the contribution of cytogenetics to important neurological associates such as mental retardation (UK equivalent terminology is learning disability), dup15 (associated with joint laxity and panic disorder) or genomic disorders that are associated with clear behavioural phenotypes such as Williams syndrome (overfriendliness and anxiety), Smith–Magenis syndrome (self-injury), Prader–Willi syndrome (hyperphagia) or chromosome 22 deletion syndrome (associated with psychosis).24, 25, 26, 27, 28 Neither shall we discuss the important work being carried out on the phenomenon of subtelomeric deletions associated with idiopathic mental retardation29, 30 as well as autism.31, 32, 33, 34 . . .
  26. Finucane B, Dirrigl KH & Simon EW. Characterization of self-injurious behaviors in children and adults with Smith−Magenis syndrome. Am J Ment Retard 2001; 106: 52−58 , .
    • . . . For similar reasons, we have not included the contribution of cytogenetics to important neurological associates such as mental retardation (UK equivalent terminology is learning disability), dup15 (associated with joint laxity and panic disorder) or genomic disorders that are associated with clear behavioural phenotypes such as Williams syndrome (overfriendliness and anxiety), Smith–Magenis syndrome (self-injury), Prader–Willi syndrome (hyperphagia) or chromosome 22 deletion syndrome (associated with psychosis).24, 25, 26, 27, 28 Neither shall we discuss the important work being carried out on the phenomenon of subtelomeric deletions associated with idiopathic mental retardation29, 30 as well as autism.31, 32, 33, 34 . . .
  27. Boer H, Holland A, Whittington J, Butler J, Webb T & Clarke D. Psychotic illness in people with Prader Willi syndrome due to chromosome 15 maternal uniparental disomy. Lancet 2002; 359: 135−136 , .
    • . . . For similar reasons, we have not included the contribution of cytogenetics to important neurological associates such as mental retardation (UK equivalent terminology is learning disability), dup15 (associated with joint laxity and panic disorder) or genomic disorders that are associated with clear behavioural phenotypes such as Williams syndrome (overfriendliness and anxiety), Smith–Magenis syndrome (self-injury), Prader–Willi syndrome (hyperphagia) or chromosome 22 deletion syndrome (associated with psychosis).24, 25, 26, 27, 28 Neither shall we discuss the important work being carried out on the phenomenon of subtelomeric deletions associated with idiopathic mental retardation29, 30 as well as autism.31, 32, 33, 34 . . .
  28. Murphy KC & Owen MJ. Velo-cardio-facial syndrome: a model for understanding the genetics and pathogenesis of schizophrenia. Br J Psychiatry 2001; 179: 397−402 , .
    • . . . For similar reasons, we have not included the contribution of cytogenetics to important neurological associates such as mental retardation (UK equivalent terminology is learning disability), dup15 (associated with joint laxity and panic disorder) or genomic disorders that are associated with clear behavioural phenotypes such as Williams syndrome (overfriendliness and anxiety), Smith–Magenis syndrome (self-injury), Prader–Willi syndrome (hyperphagia) or chromosome 22 deletion syndrome (associated with psychosis).24, 25, 26, 27, 28 Neither shall we discuss the important work being carried out on the phenomenon of subtelomeric deletions associated with idiopathic mental retardation29, 30 as well as autism.31, 32, 33, 34 . . .
  29. De Vries BB, Winter R, Schinzel A & van Ravenswaaij-Arts C. Telomeres: a diagnosis at the end of the chromosomes. J Med Genet 2003; 40: 385−398 , .
    • . . . For similar reasons, we have not included the contribution of cytogenetics to important neurological associates such as mental retardation (UK equivalent terminology is learning disability), dup15 (associated with joint laxity and panic disorder) or genomic disorders that are associated with clear behavioural phenotypes such as Williams syndrome (overfriendliness and anxiety), Smith–Magenis syndrome (self-injury), Prader–Willi syndrome (hyperphagia) or chromosome 22 deletion syndrome (associated with psychosis).24, 25, 26, 27, 28 Neither shall we discuss the important work being carried out on the phenomenon of subtelomeric deletions associated with idiopathic mental retardation29, 30 as well as autism.31, 32, 33, 34 . . .
  30. Flint J & Knight S. The use of telomere probes to investigate submicroscopic rearrangements associated with mental retardation. Curr Opin Genet Dev 2003; 13: 310−316 , .
    • . . . For similar reasons, we have not included the contribution of cytogenetics to important neurological associates such as mental retardation (UK equivalent terminology is learning disability), dup15 (associated with joint laxity and panic disorder) or genomic disorders that are associated with clear behavioural phenotypes such as Williams syndrome (overfriendliness and anxiety), Smith–Magenis syndrome (self-injury), Prader–Willi syndrome (hyperphagia) or chromosome 22 deletion syndrome (associated with psychosis).24, 25, 26, 27, 28 Neither shall we discuss the important work being carried out on the phenomenon of subtelomeric deletions associated with idiopathic mental retardation29, 30 as well as autism.31, 32, 33, 34 . . .
  31. Gillberg C. Chromosomal disorders and autism. J Autism Dev Disord 1998; 28: 415−425 , .
  32. Lauritsen M, Mors O, Mortensen PB & Ewald H. Infantile autism and associated autosomal chromosome abnormalities: a register-based study and a literature survey. J Child Psychol Psychiatry 1999; 40: 335−345 , .
    • . . . For similar reasons, we have not included the contribution of cytogenetics to important neurological associates such as mental retardation (UK equivalent terminology is learning disability), dup15 (associated with joint laxity and panic disorder) or genomic disorders that are associated with clear behavioural phenotypes such as Williams syndrome (overfriendliness and anxiety), Smith–Magenis syndrome (self-injury), Prader–Willi syndrome (hyperphagia) or chromosome 22 deletion syndrome (associated with psychosis).24, 25, 26, 27, 28 Neither shall we discuss the important work being carried out on the phenomenon of subtelomeric deletions associated with idiopathic mental retardation29, 30 as well as autism.31, 32, 33, 34 . . .
  33. Goizet C, Excoffier E, Taine L, Taupiac E, El Moneim AA & Arveiler B et al.. Case with autistic syndrome and chromosome 22q13.3 deletion detected by FISH. Am J Med Genet 2000; 96: 839−844 , .
    • . . . For similar reasons, we have not included the contribution of cytogenetics to important neurological associates such as mental retardation (UK equivalent terminology is learning disability), dup15 (associated with joint laxity and panic disorder) or genomic disorders that are associated with clear behavioural phenotypes such as Williams syndrome (overfriendliness and anxiety), Smith–Magenis syndrome (self-injury), Prader–Willi syndrome (hyperphagia) or chromosome 22 deletion syndrome (associated with psychosis).24, 25, 26, 27, 28 Neither shall we discuss the important work being carried out on the phenomenon of subtelomeric deletions associated with idiopathic mental retardation29, 30 as well as autism.31, 32, 33, 34 . . .
  34. Manning MA, Cassidy SB, Clericuzio C, Cherry AM, Schwartz S & Hudgins L et al.. Terminal 22q deletion syndrome: a newly recognized cause of speech and language disability in the autism spectrum. Pediatrics 2004; 114: 451−457 , .
  35. Tentler D, Johannesson T, Johansson M, Rastam M, Gillberg C & Orsmark C et al.. A candidate region for Asperger syndrome defined by two 17p breakpoints. Eur J Hum Genet 2003; 11: 189−195 , .
  36. Castermans D, Wilquet V, Parthoens E, Huysmans C, Steyaert J & Swinnen L et al.. The neurobeachin gene is disrupted by a translocation in a patient with idiopathic autism. J Med Genet 2003; 40: 352−356 , .
  37. Wang X, Herberg FW, Laue MM, Wullner C, Hu B & Petrasch-Parwez E et al.. Neurobeachin: a protein kinase A-anchoring, beige/Chediak-higashi protein homolog implicated in neuronal membrane traffic. J Neurosci 2000; 20: 8551−8565 , .
  38. Vincent JB, Herbrick JA, Gurling HM, Bolton PF, Roberts W & Scherer SW. Identification of a novel gene on chromosome 7q31 that is interrupted by a translocation breakpoint in an autistic individual. Am J Hum Genet 2000; 67: 510−514 , .
  39. Vincent JB, Petek E, Thevarkunnel S, Kolozsvari D, Cheung J & Patel M et al.. The RAY1/ST7 tumor-suppressor locus on chromosome 7q31 represents a complex multi-transcript system. Genomics 2002; 80: 283−294 , .
  40. Sultana R, Yu CE, Yu J, Munson J, Chen D & Hua W et al.. Identification of a novel gene on chromosome 7q11.2 interrupted by a translocation breakpoint in a pair of autistic twins. Genomics 2002; 80: 129−134 , .
  41. Tentler D, Brandberg G, Betancur C, Gillberg C, Anneren G & Orsmark C et al.. A balanced reciprocal translocation t(5;7)(q14;q32) associated with autistic disorder: molecular analysis of the chromosome 7 breakpoint. Am J Med Genet 2001; 105: 729−736 , .
  42. Ishikawa-Brush Y, Powell JF, Bolton P, Miller AP, Francis F & Willard HF et al.. Autism and multiple exostoses associated with an X;8 translocation occurring within the GRPR gene and 3' to the SDC2 gene. Hum Mol Genet 1997; 6: 1241−1250 , .
  43. Petek E, Windpassinger C, Vincent JB, Cheung J, Boright AP & Scherer SW et al.. Disruption of a novel gene (IMMP2L) by a breakpoint in 7q31 associated with Tourette syndrome. Am J Hum Genet 2001; 68: 848−858 , .
  44. Verkerk AJ, Mathews CA, Joosse M, Eussen BH, Heutink P & Oostra BA. Tourette Syndrome Association International Consortium for Genetics. CNTNAP2 is disrupted in a family with Gilles de la Tourette syndrome and obsessive−compulsive disorder. Genomics 2003; 82: 1−9 , .
  45. Nakabayashi K & Scherer SW. The human contactin-associated protein-like 2 gene (CNTNAP2) spans over 2 Mb of DNA at chromosome 7q35. Genomics 2001; 73: 108−112 , .
  46. Taipale M, Kaminen N, Nopola-Hemmi J, Haltia T, Myllyluoma B & Lyytinen H et al.. A candidate gene for developmental dyslexia encodes a nuclear tetratricopeptide repeat domain protein dynamically regulated in brain. Proc Natl Acad Sci USA 2003; 100: 11553−11558 , .
  47. Lai CS, Fisher SE, Hurst JA, Vargha-Khadem F & Monaco AP. A forkhead-domain gene is mutated in a severe speech and language disorder. Nature 2001; 413: 519−523 , .
  48. Newbury DF, Bonora E, Lamb JA, Fisher SE, Lai CS & Baird G et al.. International Molecular Genetic Study of Autism Consortium. FOXP2 is not a major susceptibility gene for autism or specific language impairment. Am J Hum Genet 2002; 70: 1318−1327 , .
  49. Lai CS, Gerrelli D, Monaco AP, Fisher SE & Copp AJ. FOXP2 expression during brain development coincides with adult sites of pathology in a severe speech and language disorder. Brain 2003; 126: 2455−2462 , .
  50. Kamnasaran D, Muir WJ, Ferguson-Smith MA & Cox DW. Disruption of the neuronal PAS3 gene in a family affected with schizophrenia. J Med Genet 2003; 40: 325−332 , .
  51. Pickard BS, Malloy MP, Porteous DJ, Blackwood DHR & Muir WJ. Disruption of a brain transcription factor, NPAS3, is associated with schizophrenia and learning disability. Am J Med Gen (in press) , .
  52. Brunskill EW, Witte DP, Shreiner AB & Potter SS. Characterization of npas3, a novel basic helix−loop−helix PAS gene expressed in the developing mouse nervous system. Mech Dev 1999; 88: 237−241 , .
  53. Millar JK, Wilson-Annan JC, Anderson S, Christie S, Taylor MS & Semple CA et al.. Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum Mol Genet 2000; 9: 1415−1423 , .
  54. Pickard BS, Malloy MP, MacIntyre DJ, Hampson RM, Porteous DJ & Blackwood DHR et al.. Disruption of an N-linked glycosylation pathway enzyme, MGAT5, in a patient with schizophrenia and learning disability. (in preparation) , .
  55. Dennis JW, Pawling J, Cheung P, Partridge E & Demetriou M. UDP-N-acetylglucosamine:alpha-6-D-mannoside beta1,6 N-acetylglucosaminyltransferase V (Mgat5) deficient mice. Biochim Biophys Acta 2002; 1573: 414−422 , .
  56. Granovsky M, Fata J, Pawling J, Muller WJ, Khokha R & Dennis JW. Suppression of tumor growth and metastasis in Mgat5-deficient mice. Nat Med 2000; 6: 306−312 , .
  57. Gecz J, Barnett S, Liu J, Hollway G, Donnelly A & Eyre H et al.. Characterization of the human glutamate receptor subunit 3 gene (GRIA3), a candidate for bipolar disorder and nonspecific X-linked mental retardation. Genomics 1999; 62: 356−368 , .
  58. Liu QJ, Gong YQ, Chen BX, Guo CH, Li JX & Guo YS. Linkage analysis and mutation detection of GRIA3 in Smith−Fineman−Myers syndrome. Yi Chuan Xue Bao 2001; 28: 985−990 , .
  59. Baysal BE, Willett-Brozick JE, Badner JA, Corona W, Ferrell RE & Nimgaonkar VL et al.. A mannosyltransferase gene at 11q23 is disrupted by a translocation breakpoint that co-segregates with bipolar affective disorder in a small family. Neurogenetics 2002; 4: 43−53 , .
  60. Link , .
  61. Blackwood DH, Fordyce A, Walker MT, St Clair DM, Porteous DJ & Muir WJ. 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 2001; 69: 428−433 , .
    • . . . In this case, an LOD score of 7.1 confirmed linkage between the translocation and illness in this family.61 Alternatively multiple independent observations of a rearrangement affecting a particular gene as reported for SATB2 in cleft palate would be good evidence of its involvement.62 Owing to the large number of genes presumably involved and the small number of reported rearrangements, it is perhaps not surprising that independent reports of disruptions to the same gene have yet to be reported for neuropsychiatric conditions . . .
    • . . . In this family, a balanced (1;11)(q42;q14) translocation cosegregates with psychosis, generating a highly significant maximum LOD score of 7.1.61, 76 Thus, in this family, translocation-induced gene disruption is causal, and a genetic locus of major effect is responsible for the psychosis in family members . . .
  62. FitzPatrick DR, Carr IM, McLaren L, Leek JP, Wightman P & Williamson K et al.. Identification of SATB2 as the cleft palate gene on 2q32−q33. Hum Mol Genet 2003; 12: 2491−2501 , .
    • . . . In this case, an LOD score of 7.1 confirmed linkage between the translocation and illness in this family.61 Alternatively multiple independent observations of a rearrangement affecting a particular gene as reported for SATB2 in cleft palate would be good evidence of its involvement.62 Owing to the large number of genes presumably involved and the small number of reported rearrangements, it is perhaps not surprising that independent reports of disruptions to the same gene have yet to be reported for neuropsychiatric conditions . . .
  63. Taddei I, Morishima M, Huynh T & Lindsay EA. Genetic factors are major determinants of phenotypic variability in a mouse model of the DiGeorge/del22q11 syndromes. Proc Natl Acad Sci USA 2001; 98: 11428−11431 , .
  64. MacIntyre DJ, Blackwood DH, Porteous DJ, Pickard BS & Muir WJ. Chromosomal abnormalities and mental illness. Mol Psychiatry 2003; 8: 275−287 , .
    • . . . In a recently collated list of published chromosome abnormalities associated with psychiatric illness, few of which have been studied at the molecular level, 22 cases match our criteria for selection based on phenotype and rearrangement type.64 Of these, diagnoses of schizophrenia and related conditions occurred far more commonly than bipolar/unipolar disorders . . .
  65. Bugge M, Bruun-Petersen G, Brondum-Nielsen K, Friedrich U, Hansen J & Jensen G et al.. Disease associated balanced chromosome rearrangements: a resource for large scale genotype−phenotype delineation in man. J Med Genet 2000; 37: 858−865 , .
    • . . . Moreover, a network of Scandinavian cytogenetics laboratories has compiled data summarising 71 739 postnatal cytogenetic tests, of which 216 showed balanced chromosome rearrangements.65 Of these, five were associated with psychotic mental illness and three with autism . . .
  66. Niculescu AB, III, Segal DS, Kuczenski R, Barrett T, Hauger RL & Kelsoe JR. Identifying a series of candidate genes for mania and psychosis: a convergent functional genomics approach. Physiol Genom 2000; 4: 83−91 , .
    • . . . Indeed, a derived classification of susceptibility genes into 'psychogenes' and 'psychosis suppressor' genes has already been proposed for psychiatric conditions.66 Therefore, cytogenetics may help to identify the 'suppressor' type of gene implicated in the aetiology of a subset of neuropsychiatric conditions. . . .
  67. Doody GA, Johnstone EC, Sanderson TL, Owens DG & Muir WJ. Pfropfschizophrenie' revisited. Schizophrenia in people with mild learning disability. Br J Psychiatry 1998; 173: 145−153 , .
    • . . . Individuals with mental retardation are more likely to have psychiatric illness than the general population67 and to have a contiguous gene syndrome, resulting from the hemizygous loss or gain of several genes simultaneously through microdeletions and duplications . . .
  68. Belsham B. Glutamate and its role in psychiatric illness. Hum Psychopharmacol 2001; 16: 139−146 , .
    • . . . The glutamate hypothesis, primarily applied to schizophrenia and related psychoses, was initially based on the observation that administration of phencyclidine and ketamine, antagonists of the NMDA subtype of glutamate receptor, can produce schizophrenia-like states.68 The hypothesis has been strengthened by recent functional and behavioural data from transgenic knockdown experiments on an NMDA receptor gene (Grin1) in mice.69 Loss-of-function mutants of glutamate receptors by cytogenetic disruption might be expected to have similar phenotypes. . . .
  69. Mohn AR, Gainetdinov RR, Caron MG & Koller BH. Mice with reduced NMDA receptor expression display behaviors related to schizophrenia. Cell 1999; 98: 427−436 , .
    • . . . The glutamate hypothesis, primarily applied to schizophrenia and related psychoses, was initially based on the observation that administration of phencyclidine and ketamine, antagonists of the NMDA subtype of glutamate receptor, can produce schizophrenia-like states.68 The hypothesis has been strengthened by recent functional and behavioural data from transgenic knockdown experiments on an NMDA receptor gene (Grin1) in mice.69 Loss-of-function mutants of glutamate receptors by cytogenetic disruption might be expected to have similar phenotypes. . . .
  70. Vogelstein B, Lane D & Levine AJ. Surfing the p53 network. Nature 2000; 408: 307−310 , .
  71. Barabasi AL & Oltvai ZN. Network biology: understanding the cell's functional organization. Nat Rev Genet 2004; 5: 101−113 (review) , .
  72. Freeze HH. Human disorders in N-glycosylation and animal models. Biochim Biophys Acta 2002; 1573: 388−393 , .
    • . . . Several other genes in this pathway have been shown to be causative for a varied group of disorders collectively known as congenital disorders of glycosylation or CDGs.72, 73 These, predominantly recessive, disorders are often characterised by central nervous system phenotypes, suggesting that the brain is particularly susceptible to perturbations in protein glycosylation.74 With a large set of target proteins predicted to be affected by these disorders, it is not hard to see how N-linked glycosylation enzymes might act as modifiers of other gene defects . . .
  73. Grunewald S, Matthijs G & Jaeken J. Congenital disorders of glycosylation: a review. Pediatr Res 2002; 52: 618−624 , .
    • . . . Several other genes in this pathway have been shown to be causative for a varied group of disorders collectively known as congenital disorders of glycosylation or CDGs.72, 73 These, predominantly recessive, disorders are often characterised by central nervous system phenotypes, suggesting that the brain is particularly susceptible to perturbations in protein glycosylation.74 With a large set of target proteins predicted to be affected by these disorders, it is not hard to see how N-linked glycosylation enzymes might act as modifiers of other gene defects . . .
  74. Yamaguchi Y. Glycobiology of the synapse: the role of glycans in the formation, maturation, and modulation of synapses. Biochim Biophys Acta 2002; 1573: 369−376 , .
    • . . . Several other genes in this pathway have been shown to be causative for a varied group of disorders collectively known as congenital disorders of glycosylation or CDGs.72, 73 These, predominantly recessive, disorders are often characterised by central nervous system phenotypes, suggesting that the brain is particularly susceptible to perturbations in protein glycosylation.74 With a large set of target proteins predicted to be affected by these disorders, it is not hard to see how N-linked glycosylation enzymes might act as modifiers of other gene defects . . .
  75. Jeffries AR, Mungall AJ, Dawson E, Halls K, Langford CF & Murray RM et al.. Beta-1,3-glucuronyltransferase-1 gene implicated as a candidate for a schizophrenia-like psychosis through molecular analysis of a balanced translocation. Mol Psychiatry 2003; 8: 654−663 , .
  76. St Clair D, Blackwood D, Muir W, Carothers A, Walker M & Spowart G et al.. Association within a family of a balanced autosomal translocation with major mental illness. Lancet 1990; 336: 13−16 , .
    • . . . In this family, a balanced (1;11)(q42;q14) translocation cosegregates with psychosis, generating a highly significant maximum LOD score of 7.1.61, 76 Thus, in this family, translocation-induced gene disruption is causal, and a genetic locus of major effect is responsible for the psychosis in family members . . .
  77. Millar JK, Christie S, Anderson S, Lawson D, Hsiao-Wei Loh D & Devon RS et al.. Genomic structure and localisation within a linkage hotspot of disrupted in schizophrenia 1, a gene disrupted by a translocation segregating with schizophrenia. Mol Psychiatry 2001; 6: 173−178 , .
  78. Ekelund J, Hovatta I, Parker A, Paunio T, Varilo T & Martin R et al.. Chromosome 1 loci in Finnish schizophrenia families. Hum Mol Genet 2001; 10: 1611−1617 , .
    • . . . A genome-wide linkage study and subsequent follow-up studies using dense marker sets identified a peak of linkage with a polymorphism that lies within DISC1 itself, with a maximum LOD score of 3.2.78 Several associated haplotypes have been identified within the same population.79 Other reports of linkage to this region include studies of North American, Taiwanese, British and Icelandic families diagnosed variously with schizophrenia and affective disorders.80, 81, 82 Both of these clinical phenotypes are expressed in the family segregating for the translocation . . .
  79. Hennah W, Varilo T, Kestila M, Paunio T, Arajarvi R & Haukka J et al.. Haplotype transmission analysis provides evidence of association for DISC1 to schizophrenia and suggests sex-dependent effects. Hum Mol Genet 2003; 12: 3151−3159 , .
    • . . . A genome-wide linkage study and subsequent follow-up studies using dense marker sets identified a peak of linkage with a polymorphism that lies within DISC1 itself, with a maximum LOD score of 3.2.78 Several associated haplotypes have been identified within the same population.79 Other reports of linkage to this region include studies of North American, Taiwanese, British and Icelandic families diagnosed variously with schizophrenia and affective disorders.80, 81, 82 Both of these clinical phenotypes are expressed in the family segregating for the translocation . . .
  80. Gejman PV, Martinez M, Cao Q, Friedman E, Berrettini WH & Goldin LR et al.. Linkage analysis of fifty-seven microsatellite loci to bipolar disorder. Neuropsychopharmacology 1993; 9: 31−40 , .
    • . . . A genome-wide linkage study and subsequent follow-up studies using dense marker sets identified a peak of linkage with a polymorphism that lies within DISC1 itself, with a maximum LOD score of 3.2.78 Several associated haplotypes have been identified within the same population.79 Other reports of linkage to this region include studies of North American, Taiwanese, British and Icelandic families diagnosed variously with schizophrenia and affective disorders.80, 81, 82 Both of these clinical phenotypes are expressed in the family segregating for the translocation . . .
  81. Hwu HG, Liu CM, Fann CS, Ou-Yang WC & Lee SF. Linkage of schizophrenia with chromosome 1q loci in Taiwanese families. Mol Psychiatry 2003; 8: 445−452 , .
    • . . . A genome-wide linkage study and subsequent follow-up studies using dense marker sets identified a peak of linkage with a polymorphism that lies within DISC1 itself, with a maximum LOD score of 3.2.78 Several associated haplotypes have been identified within the same population.79 Other reports of linkage to this region include studies of North American, Taiwanese, British and Icelandic families diagnosed variously with schizophrenia and affective disorders.80, 81, 82 Both of these clinical phenotypes are expressed in the family segregating for the translocation . . .
  82. Curtis D, Kalsi G, Brynjolfsson J, McInnis M, O'Neill J & Smyth C et al.. Genome scan of pedigrees multiply affected with bipolar disorder provides further support for the presence of a susceptibility locus on chromosome 12q23−q24, and suggests the presence of additional loci on 1p and 1q. Psychiatr Genet 2003; 13: 77−84 , .
    • . . . A genome-wide linkage study and subsequent follow-up studies using dense marker sets identified a peak of linkage with a polymorphism that lies within DISC1 itself, with a maximum LOD score of 3.2.78 Several associated haplotypes have been identified within the same population.79 Other reports of linkage to this region include studies of North American, Taiwanese, British and Icelandic families diagnosed variously with schizophrenia and affective disorders.80, 81, 82 Both of these clinical phenotypes are expressed in the family segregating for the translocation . . .
  83. Austin CP, Ma L, Ky B, Morris JA & Shughrue PJ. DISC1 (disrupted in schizophrenia-1) is expressed in limbic regions of the primate brain. Neuroreport 2003; 14: 951−954 , .
    • . . . In particular, DISC1 is expressed in the hippocampus and limbic regions of the adult brain83 and its possible involvement in neurodevelopmental processes has been highlighted by its interaction with other proteins including FEZ184 and Nudel.85, 86, 87, 88 FEZ1 is thought to function in axon outgrowth and is associated with DISC1 at axon growth cones, suggesting a requirement for DISC1 in neurite extension, a process critical for synaptic connectivity.84 Interaction between DISC1 and Nudel suggests an additional significant neurodevelopmental role because Nudel complexes with LIS1, a molecule required for neuronal migration and cortical lamination . . .
  84. Miyoshi K, Honda A, Baba K, Taniguchi M, Oono K & Fujita T et al.. Disrupted-in-schizophrenia 1, a candidate gene for schizophrenia, participates in neurite outgrowth. Mol Psychiatry 2003; 8: 685−694 , .
    • . . . In particular, DISC1 is expressed in the hippocampus and limbic regions of the adult brain83 and its possible involvement in neurodevelopmental processes has been highlighted by its interaction with other proteins including FEZ184 and Nudel.85, 86, 87, 88 FEZ1 is thought to function in axon outgrowth and is associated with DISC1 at axon growth cones, suggesting a requirement for DISC1 in neurite extension, a process critical for synaptic connectivity.84 Interaction between DISC1 and Nudel suggests an additional significant neurodevelopmental role because Nudel complexes with LIS1, a molecule required for neuronal migration and cortical lamination . . .
  85. Millar JK, Christie S & Porteous DJ. Yeast two-hybrid screens implicate DISC1 in brain development and function. Biochem Biophys Res Commun 2003; 311: 1019−1025 , .
    • . . . In particular, DISC1 is expressed in the hippocampus and limbic regions of the adult brain83 and its possible involvement in neurodevelopmental processes has been highlighted by its interaction with other proteins including FEZ184 and Nudel.85, 86, 87, 88 FEZ1 is thought to function in axon outgrowth and is associated with DISC1 at axon growth cones, suggesting a requirement for DISC1 in neurite extension, a process critical for synaptic connectivity.84 Interaction between DISC1 and Nudel suggests an additional significant neurodevelopmental role because Nudel complexes with LIS1, a molecule required for neuronal migration and cortical lamination . . .
  86. Ozeki Y, Tomoda T, Kleiderlein J, Kamiya A, Bord L & Fujii K et al.. Disrupted-in-schizophrenia-1 (DISC-1): mutant truncation prevents binding to NudE-like (NUDEL) and inhibits neurite outgrowth. Proc Natl Acad Sci USA 2003; 100: 289−294 , .
    • . . . In particular, DISC1 is expressed in the hippocampus and limbic regions of the adult brain83 and its possible involvement in neurodevelopmental processes has been highlighted by its interaction with other proteins including FEZ184 and Nudel.85, 86, 87, 88 FEZ1 is thought to function in axon outgrowth and is associated with DISC1 at axon growth cones, suggesting a requirement for DISC1 in neurite extension, a process critical for synaptic connectivity.84 Interaction between DISC1 and Nudel suggests an additional significant neurodevelopmental role because Nudel complexes with LIS1, a molecule required for neuronal migration and cortical lamination . . .
  87. Morris JA, Kandpal G, Ma L & Austin CP. DISC1 (disrupted-in-schizophrenia 1) is a centrosome-associated protein that interacts with MAP1A, MIPT3, ATF4/5 and NUDEL: regulation and loss of interaction with mutation. Hum Mol Genet 2003; 12: 1591−1608 , .
    • . . . In particular, DISC1 is expressed in the hippocampus and limbic regions of the adult brain83 and its possible involvement in neurodevelopmental processes has been highlighted by its interaction with other proteins including FEZ184 and Nudel.85, 86, 87, 88 FEZ1 is thought to function in axon outgrowth and is associated with DISC1 at axon growth cones, suggesting a requirement for DISC1 in neurite extension, a process critical for synaptic connectivity.84 Interaction between DISC1 and Nudel suggests an additional significant neurodevelopmental role because Nudel complexes with LIS1, a molecule required for neuronal migration and cortical lamination . . .
  88. Brandon NJ, Handford EJ, Schurov I, Rain J-C, Pelling M & Duran-Jimeniz B et al.. Disrupted in schizophrenia 1 and Nudel form a neurodevelopmentally regulated protein complex: implications for schizophrenia and other major neurological disorders. Mol Cell Neurosci 2004; 25: 42−55 , .
    • . . . In particular, DISC1 is expressed in the hippocampus and limbic regions of the adult brain83 and its possible involvement in neurodevelopmental processes has been highlighted by its interaction with other proteins including FEZ184 and Nudel.85, 86, 87, 88 FEZ1 is thought to function in axon outgrowth and is associated with DISC1 at axon growth cones, suggesting a requirement for DISC1 in neurite extension, a process critical for synaptic connectivity.84 Interaction between DISC1 and Nudel suggests an additional significant neurodevelopmental role because Nudel complexes with LIS1, a molecule required for neuronal migration and cortical lamination . . .
  89. Cardon LR & Bell JI. Association study designs for complex diseases. Nat Rev Genet 2001; 2: 91−99 , .
    • . . . Common disorders with a strong genetic basis, including psychiatric illnesses can be modelled as being due to additive or interactive effects of functionally important, relatively common genetic variants that have incomplete penetrance and small effects at the population level (odds ratio <2): referred to as the 'common disease, common variant' hypothesis.2, 89 Another situation, illustrated by mutations in the APC gene that causes colorectal polyps, is that a number of rare mutations of high penetrance at different sites in a single gene have an additive effect in causing disease.90 Similar rare variants may be typical in many complex disorders including mental disease.91 A third possibility is locus heterogeneity, illustrated by the genetic basis of nonsyndromic deafness, where the phenotype is caused by a mutation with high penetrance in one of very many genes.92 The genes included in Table 1 in this study are possibly illustrative of the locus heterogeneity model. . . .
  90. Frayling IM, Beck NE, Ilyas M, Dove-Edwin I, Goodman P & Pack K et al.. The APC variants I1307K and E1317Q are associated with colorectal tumors, but not always with a family history. Proc Natl Acad Sci USA 1998; 95: 10722−10727 , .
    • . . . Common disorders with a strong genetic basis, including psychiatric illnesses can be modelled as being due to additive or interactive effects of functionally important, relatively common genetic variants that have incomplete penetrance and small effects at the population level (odds ratio <2): referred to as the 'common disease, common variant' hypothesis.2, 89 Another situation, illustrated by mutations in the APC gene that causes colorectal polyps, is that a number of rare mutations of high penetrance at different sites in a single gene have an additive effect in causing disease.90 Similar rare variants may be typical in many complex disorders including mental disease.91 A third possibility is locus heterogeneity, illustrated by the genetic basis of nonsyndromic deafness, where the phenotype is caused by a mutation with high penetrance in one of very many genes.92 The genes included in Table 1 in this study are possibly illustrative of the locus heterogeneity model. . . .
  91. Botstein D & Risch N. Discovering genotypes underlying human phenotypes: past successes for Mendelian disease, future approaches for complex disease. Nat Genet 2003; 33: 228−237 , .
    • . . . Common disorders with a strong genetic basis, including psychiatric illnesses can be modelled as being due to additive or interactive effects of functionally important, relatively common genetic variants that have incomplete penetrance and small effects at the population level (odds ratio <2): referred to as the 'common disease, common variant' hypothesis.2, 89 Another situation, illustrated by mutations in the APC gene that causes colorectal polyps, is that a number of rare mutations of high penetrance at different sites in a single gene have an additive effect in causing disease.90 Similar rare variants may be typical in many complex disorders including mental disease.91 A third possibility is locus heterogeneity, illustrated by the genetic basis of nonsyndromic deafness, where the phenotype is caused by a mutation with high penetrance in one of very many genes.92 The genes included in Table 1 in this study are possibly illustrative of the locus heterogeneity model. . . .
  92. Pritchard JK. Are rare variants responsible for susceptibility to complex diseases? Am J Hum Genet 2001; 69: 124−137 , .
    • . . . Common disorders with a strong genetic basis, including psychiatric illnesses can be modelled as being due to additive or interactive effects of functionally important, relatively common genetic variants that have incomplete penetrance and small effects at the population level (odds ratio <2): referred to as the 'common disease, common variant' hypothesis.2, 89 Another situation, illustrated by mutations in the APC gene that causes colorectal polyps, is that a number of rare mutations of high penetrance at different sites in a single gene have an additive effect in causing disease.90 Similar rare variants may be typical in many complex disorders including mental disease.91 A third possibility is locus heterogeneity, illustrated by the genetic basis of nonsyndromic deafness, where the phenotype is caused by a mutation with high penetrance in one of very many genes.92 The genes included in Table 1 in this study are possibly illustrative of the locus heterogeneity model. . . .
Expand