Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Feature Review
  • Published:

Ten Years of Molecular Psychiatry

Excitement and confusion on chromosome 6q: the challenges of neuropsychiatric genetics in microcosm

Molecular Psychiatry volume 10, pages 1062–1073 (2005)Cite this article

Abstract

The search for genes that are implicated in the pathogenesis of schizophrenia (SCZ), bipolar disorder (BPD) and other complex neuropsychiatric phenotypes has yielded a plethora of positive findings, but has also engendered a substantial degree of confusion. Exciting findings include positive linkage results in a number of chromosomal regions and the identification of several genes that have been associated with SCZ and to a lesser extent with BPD. Confusing aspects include the difference between studies in localization of linkage peaks in the same chromosomal regions, raising the possibility that these regions may harbor more than one gene, the fact that positive linkage findings as well as associated genes appear in several cases to be shared by more than one disorder, and the failure to identify thus far the precise pathogenic variants in associated genes. Recent findings of linkage and association studies on chromosome 6q illustrate the current status of neuropsychiatric genetics in intriguing microcosm. Positive findings from linkage and association studies are reviewed in order to identify approaches that may help to settle apparent contradictions and allow an interpretation of the results that may prove useful in application to findings from other chromosomal regions. Not only SCZ and BPD but also other psychiatric and neurological phenotypes are considered. Taking a topographic approach, we identify five foci of positive findings on chromosome 6q and suggest that each may harbor gene(s) that confer susceptibility to SCZ or BPD or may modify their onset or clinical course. We further suggest that in searching for these genes the possibility that they may be implicated in more than one disorder should be taken into account. We also discuss the potential contribution of rare genetic variants identified in homogeneous, isolated populations to the subsequent identification of common variants in the same gene that contribute to disease susceptibility in outbred populations.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

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

    Article  CAS  Google Scholar 

  2. Berrettini WH . Molecular linkage studies of bipolar disorders. Bipolar Disord 2001; 3: 276–283.

    Article  CAS  Google Scholar 

  3. Kohn Y, Lerer B . Genetics of schizophrenia—linkage findings: a review. Israel J Psychiatr Rel Sci 2002; 39: 240–251.

    Google Scholar 

  4. Mathews CA, Reus VI . Genetic linkage in bipolar disorder. CNS Spectr 2003; 8: 891–904.

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  6. Lewis CM, Levinson DF, Wise LH, DeLisi LE, Straub RE, Hovatta I et al. Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia. Am J Hum Genet 2003; 73: 34–48.

    Article  CAS  Google Scholar 

  7. Segurado R, Detera-Wadleigh SD, Levinson DF, Lewis CM, Gill M, Nurnberger Jr JI et al. Genome scan meta-analysis of schizophrenia and bipolar disorder, part III: Bipolar disorder. Am J Hum Genet 2003; 73: 49–62.

    Article  CAS  Google Scholar 

  8. Straub R, Jiang Y, MacLean C, Ma Y, Webb B, Myakishev M 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.

    Article  CAS  Google Scholar 

  9. Stefansson H, Sigurdsson E, Steinthorsdottir V, Bjornsdottir S, Sigmundsson T, Ghosh S et al. Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet 2002; 71: 877–892.

    Article  Google Scholar 

  10. Shifman S, Bronstein M, Sternfeld M, Pisante-Shalom A, Lev-Lehman E, Weizman A et al. A highly significant association between a COMT haplotype and schizophrenia. Am J Hum Genet 2002; 71: 1296–1302.

    Article  CAS  Google Scholar 

  11. Chumakov I, Blumenfeld M, Guerassimenko O, Cavarec L, Palicio M, Abderrahim H 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 USA 2002; 99: 13675–13680.

    Article  CAS  Google Scholar 

  12. Hattori E, Liu C, Badner J, Bonner T, Christian S, Maheshwari M et al. Polymorphisms at the g72/g30 gene locus, on 13q33, are associated with bipolar disorder in two independent pedigree series. Am J Hum Genet 2003; 72: 1131–1140.

    Article  CAS  Google Scholar 

  13. Chen Q, He G, Wang XY, Chen QY, Liu XM, Gu ZZ et al. Positive association between synapsin II and schizophrenia. Biol Psychiatry 2004; 56: 177–181.

    Article  CAS  Google Scholar 

  14. Duan J, Martinez M, Sanders AR, Hou C, Saitou N, Kitano T et al. Polymorphisms in the trace amine receptor 4 (TRAR4) gene on chromosome 6q23.2 are associated with susceptibility to schizophrenia. Am J Hum Genet 2004; 75: 624–638.

    Article  CAS  Google Scholar 

  15. 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.

    Article  CAS  Google Scholar 

  16. Prasad S, Chowdari KV, Wood J, Bhatia T, Deshpande SN, Nimgaonkar VL et al. Association analysis of NOTCH 4 polymorphisms with schizophrenia among two independent family based samples. Am J Med Genet B Neuropsychiatr Genet 2004; 131: 6–9.

    Article  Google Scholar 

  17. Pimm J, McQuillin A, Thirumalai S, Lawrence J, Quested D, Bass N et al. The epsin 4 gene on chromosome 5q, which encodes the clathrin-associated protein enthoprotin, is involved in the genetic susceptibility to schizophrenia. Am J Hum Genet 2005; 76: 902–907.

    Article  CAS  Google Scholar 

  18. Brzustowicz LM, Honer WG, Chow EW, Little D, Hogan J, Hodgkinson K et al. Linkage of familial schizophrenia to chromosome 13q32. Am J Hum Genet 1999; 65: 1096–1103.

    Article  CAS  Google Scholar 

  19. Kendler KS . Schizophrenia genetics and dysbindin: a corner turned? Am J Psychiatry 2004; 161: 1533–1536.

    Article  Google Scholar 

  20. Kakiuchi C, Iwamoto K, Ishiwata M, Bundo M, Kasahara T, Kusumi I et al. Impaired feedback regulation of XBP1 as a genetic risk factor for bipolar disorder. Nat Genet 2003; 35: 171–175.

    Article  CAS  Google Scholar 

  21. Liu H, Heath SC, Sobin C, Roos JL, Galke BL, Blundell ML et al. Genetic variation at the 22q11 PRODH2/DGCR6 locus presents an unusual pattern and increases susceptibility to schizophrenia. Proc Natl Acad Sci USA 2002; 99: 3717–3722.

    Article  CAS  Google Scholar 

  22. Berrettini W . Evidence for shared susceptibility in bipolar disorder and schizophrenia. Am J Med Genet 2003; 123C: 59–64.

    Article  Google Scholar 

  23. Shifman S, Bronstein M, Sternfeld M, Pisante A, Weizman A, Reznik I et al. COMT: a common susceptibility gene in bipolar disorder and schizophrenia. Am J Med Genet 2004; 128B: 61–64.

    Article  Google Scholar 

  24. Cao Q, Martinez M, Zhang J, Sanders AR, Badner JA, Cravchik A et al. Suggestive evidence for a schizophrenia susceptibility locus on chromosome 6q and a confirmation in an independent series of pedigrees. Genomics 1997; 43: 1–8.

    Article  CAS  Google Scholar 

  25. Martinez M, Goldin LR, Cao Q, Zhang J, Sanders AR, Nancarrow DJ et al. Follow-up study on a susceptibility locus for schizophrenia on chromosome 6q. Am J Med Genet 1999; 88: 337–343.

    Article  CAS  Google Scholar 

  26. Kaufmann CA, Suarez B, Malaspina D, Pepple J, Svrakic D, Markel PD et al. NIMH Genetics Initiative Millenium Schizophrenia Consortium: linkage analysis of African-American pedigrees. Am J Med Genet 1998; 81: 282–289.

    Article  CAS  Google Scholar 

  27. Levinson DF, Holmans P, Straub RE, Owen MJ, Wildenauer DB, Gejman PV et al. Multicenter linkage study of schizophrenia candidate regions on chromosomes 5q, 6q, 10p, and 13q: schizophrenia linkage collaborative group III. Am J Hum Genet 2000; 67: 652–663.

    Article  CAS  Google Scholar 

  28. Bailer U, Leisch F, Meszaros K, Lenzinger E, Willinger U, Strobl R et al. Genome scan for susceptibility loci for schizophrenia. Neuropsychobiology 2000; 42: 175–182.

    Article  CAS  Google Scholar 

  29. Williams NM, Norton N, Williams H, Ekholm B, Hamshere ML, Lindblom Y et al. A systematic genomewide linkage study in 353 sib pairs with schizophrenia. Am J Hum Genet 2003; 73: 1355–1367.

    Article  CAS  Google Scholar 

  30. Lindholm E, Ekholm B, Shaw S, Jalonen P, Johansson G, Pettersson U et al. A schizophrenia-susceptibility locus at 6q25, in one of the world's largest reported pedigrees. Am J Hum Genet 2001; 69: 96–105.

    Article  CAS  Google Scholar 

  31. Lerer B, Segman R, Hamdan A, Kanyas K, Karni O, Kohn Y et al. Genome scan of Arab Israeli families maps a schizophrenia susceptibility gene to chromosome 6q23 and supports a locus at chromosome 10q24. Mol Psychiatry 2003; 8: 488–498.

    Article  CAS  Google Scholar 

  32. Levi A, Kohn Y, Kanyas K, Amann D, Pae CU, Hamdan A et al. Fine mapping of a schizophrenia susceptibility locus at chromosome 6q23: increased evidence for linkage and reduced linkage interval. Eur J Hum Genet 2005; 6: 6.

    Google Scholar 

  33. Ikeda M, Iwata N, Suzuki T, Kitajima T, Yamanouchi Y, Kinoshita Y et al. No association of haplotype-tagging SNPs in TRAR4 with schizophrenia in Japanese patients. Schizophr Res 2005; 19: 19.

    Google Scholar 

  34. Amann D, Avidan N, Kanyas K, Kohn Y, Hamdan A, Ben-Asher E . The trace amine receptor 4 gene is not associated with schizophrenia in a sample linked to chromosome 6q23. Mol Psychiatry, (in press).

  35. Edgar PF, Douglas JE, Cooper GJ, Dean B, Kydd R, Faull RL . Comparative proteome analysis of the hippocampus implicates chromosome 6q in schizophrenia. Mol Psychiatry 2000; 5: 85–90.

    Article  CAS  Google Scholar 

  36. Sanders AR, Gejman PV . Major corrections are indicated for ‘Comparative proteome analysis of the hippocampus implicates chromosome 6q in schizophrenia’. Mol Psychiatry 2001; 6: 10–12.

    Article  CAS  Google Scholar 

  37. Bennett P, Segurado R, Jones I, Bort S, McCandless F, Lambert D et al. The Wellcome trust UK–Irish bipolar affective disorder sibling-pair genome screen: first stage report. Mol Psychiatry 2002; 7: 189–200.

    Article  CAS  Google Scholar 

  38. Ewald H, Flint T, Kruse TA, Mors O . A genome-wide scan shows significant linkage between bipolar disorder and chromosome 12q24.3 and suggestive linkage to chromosomes 1p22–21, 4p16, 6q14–22, 10q26 and 16p13.3. Mol Psychiatry 2002; 7: 734–744.

    Article  CAS  Google Scholar 

  39. Bailer U, Leisch F, Meszaros K, Lenzinger E, Willinger U, Strobl R et al. Genome scan for susceptibility loci for schizophrenia and bipolar disorder. Biol Psychiatry 2002; 52: 40–52.

    Article  CAS  Google Scholar 

  40. McInnis MG, Dick DM, Willour VL, Avramopoulos D, MacKinnon DF, Simpson SG et al. Genome-wide scan and conditional analysis in bipolar disorder: evidence for genomic interaction in the National Institute of Mental Health genetics initiative bipolar pedigrees. Biol Psychiatry 2003; 54: 1265–1273.

    Article  CAS  Google Scholar 

  41. Rice JP, Goate A, Williams JT, Bierut L, Dorr D, Wu W et al. Initial genome scan of the NIMH genetics initiative bipolar pedigrees: chromosomes 1, 6, 8, 10, and 12. Am J Med Genet 1997; 74: 247–253.

    Article  CAS  Google Scholar 

  42. Dick DM, Foroud T, Flury L, Bowman ES, Miller MJ, Rau NL et al. Genomewide linkage analyses of bipolar disorder: a new sample of 250 pedigrees from the National Institute of Mental Health Genetics Initiative. Am J Hum Genet 2003; 73: 107–114. (erratum in Am J Hum Genet 2003; 73: 979).

    Article  CAS  Google Scholar 

  43. Schulze TG, Buervenich S, Badner JA, Steele CJ, Detera-Wadleigh SD, Dick D et al. Loci on chromosomes 6q and 6p interact to increase susceptibility to bipolar affective disorder in the national institute of mental health genetics initiative pedigrees. Biol Psychiatry 2004; 56: 18–23.

    Article  CAS  Google Scholar 

  44. Pato CN, Pato MT, Kirby A, Petryshen TL, Medeiros H, Carvalho C et al. Genome-wide scan in Portuguese Island families implicates multiple loci in bipolar disorder: fine mapping adds support on chromosomes 6 and 11. Am J Med Genet B Neuropsychiatr Genet 2004; 127: 30–34.

    Article  Google Scholar 

  45. Middleton FA, Pato MT, Gentile KL, Morley CP, Zhao X, Eisener AF et al. Genomewide linkage analysis of bipolar disorder by use of a high-density single-nucleotide-polymorphism (SNP) genotyping assay: a comparison with microsatellite marker assays and finding of significant linkage to chromosome 6q22. Am J Hum Genet 2004; 74: 886–897.

    Article  CAS  Google Scholar 

  46. Park N, Juo SH, Cheng R, Liu J, Loth JE, Lilliston B et al. Linkage analysis of psychosis in bipolar pedigrees suggests novel putative loci for bipolar disorder and shared susceptibility with schizophrenia. Mol Psychiatry 2004; 9: 1091–1099.

    Article  CAS  Google Scholar 

  47. Park N, Cheng R, Juo SH, Liu J, Loth JE, Endicott J et al. Absence of psychosis may influence linkage results for bipolar disorder. Mol Psychiatry 2005; 10: 235–237.

    Article  CAS  Google Scholar 

  48. Venken T, Claes S, Sluijs S, Paterson AD, van Duijn C, Adolfsson R et al. Genomewide scan for affective disorder susceptibility loci in families of a northern Swedish isolated population. Am J Hum Genet 2005; 76: 237–248.

    Article  CAS  Google Scholar 

  49. Abou Jamra R, Sircar I, Becker T, Freudenberg-Hua Y, Ohlraun S, Freudenberg J et al. A family-based and case–control association study of trace amine receptor genes on chromosome 6q23 in bipolar affective disorder. Mol Psychiatry 2005; 10: 618–620.

    Article  CAS  Google Scholar 

  50. Cichon S, Schumacher J, Muller DJ, Hurter M, Windemuth C, Strauch K et al. A genome screen for genes predisposing to bipolar affective disorder detects a new susceptibility locus on 8q. Hum Mol Genet 2001; 10: 2933–2944.

    Article  CAS  Google Scholar 

  51. Zubenko GS, Maher BS, Hughes III HB, Zubenko WN, Stiffler JS, Marazita ML . Genome-wide linkage survey for genetic loci that affect the risk of suicide attempts in families with recurrent, early-onset, major depression. Am J Med Genet B Neuropsychiatr Genet 2004; 129: 47–54.

    Article  Google Scholar 

  52. Philippe A, Martinez M, Guilloud-Bataille M, Gillberg C, Rastam M, Sponheim E et al. Genome-wide scan for autism susceptibility genes. Paris Autism Research International Sibpair Study. Hum Mol Genet 1999; 8: 805–812.

    Article  CAS  Google Scholar 

  53. Kenealy SJ, Babron MC, Bradford Y, Schnetz-Boutaud N, Haines JL, Rimmler JB et al. A second-generation genomic screen for multiple sclerosis. Am J Hum Genet 2004; 75: 1070–1078.

    Article  CAS  Google Scholar 

  54. Li JL, Hayden MR, Almqvist EW, Brinkman RR, Durr A, Dode C et al. A genome scan for modifiers of age at onset in Huntington disease: the HD MAPS study. Am J Hum Genet 2003; 73: 682–687.

    Article  CAS  Google Scholar 

  55. Petryshen TL, Kaplan BJ, Fu Liu M, de French NS, Tobias R, Hughes ML et al. Evidence for a susceptibility locus on chromosome 6q influencing phonological coding dyslexia. Am J Med Genet 2001; 105: 507–517.

    Article  CAS  Google Scholar 

  56. Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 1998; 392: 605–608.

    Article  CAS  Google Scholar 

  57. Ferland RJ, Eyaid W, Collura RV, Tully LD, Hill RS, Al-Nouri D et al. Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome. Nat Genet 2004; 36: 1008–1013.

    Article  CAS  Google Scholar 

  58. Dixon-Salazar T, Silhavy JL, Marsh SE, Louie CM, Scott LC, Gururaj A et al. Mutations in the AHI1 gene, encoding jouberin, cause Joubert syndrome with cortical polymicrogyria. Am J Hum Genet 2004; 75: 979–987.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  60. McQueen MB, Devlin B, Faraone SV, Nimgaonkar VL, Sklar P, Smoller JW et al. Combined analysis from eleven linkage studies of bipolar disorder provides strong evidence of susceptibility loci on chromosomes 6q and 8q. Am J Hum Genet 2005 (Epub ahead of print).

  61. Mungall AJ, Palmer SA, Sims SK, Edwards CA, Ashurst JL, Wilming L et al. The DNA sequence and analysis of human chromosome 6. Nature 2003; 425: 805–811.

    Article  CAS  Google Scholar 

  62. Angst J, Marneros A . Bipolarity from ancient to modern times: conception, birth and rebirth. J Affect Disord 2001; 67: 3–19.

    Article  CAS  Google Scholar 

  63. Crow TJ . A continuum of psychosis, one human gene, and not much else—the case for homogeneity. Schizophr Res 1995; 17: 135–145.

    Article  CAS  Google Scholar 

  64. Gottesman II, Gould TD . The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry 2003; 160: 636–645.

    Article  Google Scholar 

  65. 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.

    Article  CAS  Google Scholar 

  66. 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.

    Article  CAS  Google Scholar 

  67. Cargill M, Daley GQ . Mining for SNPs: putting the common variants—common disease hypothesis to the test. Pharmacogenomics 2000; 1: 27–37.

    Article  CAS  Google Scholar 

  68. Fanous AH, Kendler KS . Genetic heterogeneity, modifier genes, and quantitative phenotypes in psychiatric illness: searching for a framework. Mol Psychiatry 2005; 10: 6–13.

    Article  CAS  Google Scholar 

  69. Stewart DR, von Allmen D . The genetics of Hirschsprung disease. Gastroenterol Clin North Am 2003; 32: 819–837, vi.

    Article  Google Scholar 

  70. Edery P, Lyonnet S, Mulligan LM, Pelet A, Dow E, Abel L et al. Mutations of the RET proto-oncogene in Hirschsprung's disease. Nature 1994; 367: 378–380.

    Article  CAS  Google Scholar 

  71. Emison ES, McCallion AS, Kashuk CS, Bush RT, Grice E, Lin S et al. A common sex-dependent mutation in a RET enhancer underlies Hirschsprung disease risk. Nature 2005; 434: 857–863.

    Article  CAS  Google Scholar 

  72. Liu PY, Zhang YY, Lu Y, Long JR, Shen H, Zhao LJ et al. A survey of haplotype variants at several disease candidate genes: the importance of rare variants for complex diseases. J Med Genet 2005; 42: 221–227.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Professor J Beckman for his thoughtful reading of the manuscript and valuable comments. This study was supported in part by a grant from the Israel Ministry of Science and Technology (Korean-Israeli Research Cooperation) to BL.

Author information

Authors and Affiliations

  1. Department of Psychiatry, Biological Psychiatry Laboratory, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

    Y Kohn & B Lerer

Authors
  1. Y Kohn
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. B Lerer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Y Kohn.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kohn, Y., Lerer, B. Excitement and confusion on chromosome 6q: the challenges of neuropsychiatric genetics in microcosm. Mol Psychiatry 10, 1062–1073 (2005). https://doi.org/10.1038/sj.mp.4001738

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4001738

Keywords

This article is cited by

Search

Advanced search

Quick links