Abstract
Schizophrenia is thought to be a multifactorial disease with complex mode of inheritance1,2. Using a two-stage strategy for another complex disorder, a number of putative IDDM-susceptibility genes have recently been mapped3. We now report the results of a two-stage genome-wide search for genes conferring susceptibility to schizophrenia. In stage I, model-free linkage analyses of large pedigrees from Iceland, a geographical isolate, revealed 26 loci suggestive of linkage. In stage II, ten of these were followed-up in a second international collaborative study comprising families from Austria, Canada, Germany, Italy, Scotland, Sweden, Taiwan and the United States. Potential linkage findings of stage I on chromosomes 6p, 9 and 20 were observed again in the second sample. Furthermore, in a third sample from China, fine mapping of the 6p region by association studies also showed evidence for linkage or linkage disequilibrium. Combining our results with other recent findings4,5 revealed significant evidence for linkage to an area distal of the HLA region on chromosome 6p. However, in a fourth sample from Europe, the 6p fine mapping finding observed in the Chinese sample could not be replicated. Finally, evidence suggestive of locus heterogeneity and oligogenic transmission in schizophrenia was obtained.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Gottesman, I.I. Schizophrenia genesis: the origins of madness. (W.H. Freeman, 1991).
Moises, H.W. Genetic models of schizophrenia. In Advances in the Neurobiology of Schizophrenia (eds den Boer, J.A., Westenberg, H.G.M., van Praag, H.M.) 59–86 (John Wiley & Sons, New York, 1995).
Davies, J.L. et al. A genome-wide search for human type 1 diabetes susceptibility genes. Nature 371, 130–136 (1994).
Wang, S. et al. Evidence for a susceptibility locus for schizophrenia on chromosome 6pter-p22. Nature Genet. 10, 41–46 (1995).
Straub, R.E. et al. A potential vulnerability locus for schizophrenia on chromosome 6p24-22 and evidence for genetic heterogeneity. Nature Genet. 11, tk–tk.
Weissenbach, J. et al. A second-generation linkage-map of the human genome. Nature 359, 794–801 (1992).
Commenges, D., Olson, J. & Wijsman, E. The weighted rank pairwise correlation statistic for linkage analysis: simulation study and application to Alzheimer's disease. Genet. Epidemiol. 11, 201–212 (1994).
Blossey, H., Commenges, D. & Olson, J.M. Linkage analysis of Alzheimer's disease with methods using relative pairs. Genet. Epidemiol. 10, 377–383 (1993).
NIH/CEPH Collaborative Mapping Group. A comphrehensive genetic linkage map of the human genome. Science 258, 67–86 (1992).
Elston, R.C. Designs for the global search of the human genome by linkage analysis. In Proceedings of the 16th International Biometrics Conference: Hamilton, New Zealand, December 7–11, 1992. 39–51 (Ruakura Agricultural Center, Hamilton, New Zealand, 1992).
Brown, D.L., Gorin, M.B. & Weeks, D.E. Efficient strategies for genomic searching using the Affected-Pedigree-Member method for linkage analysis. Am. J. hum. Genet. 54, 544–552 (1994).
Moises, H.W. et al. Potential linkage disequilibrium between schizophrenia and locus D22S278 on the long arm of chromosome 22. Am. J. med. Genet. (in the press).
Vinogradov, S. et al. Negative association between schizophrenia and rheumatoid arthritis. Schiz. Bull. 17, 669–678 (1991).
Terwilliger, J.D. A powerful likelihood method for the analysis of linkage disequilibrium between trait loci and one or more polymorphic marker loci. Am. J. hum. Genet. 56, 777–787 (1995).
Lasseter, V.K. et al. Follow-up report of potential linkage for schizophrenia on chromosome 22q: part 3. Am. J. med. Genet. 60, 172–173 (1995).
Vallada, H.P. et al. Linkage studies on chromosome 22 in familial schizophrenia. Am. J. med. Genet. 60, 139–146 (1995).
Spitzer, R.L., Endicott, J. & Loth, J.E. Schedule for affective disorders and schizophrenia — lifetime version (SADS-LB). (New York State Psychiatric Institute, 1988).
Spitzer, R.L., Endicott, J. & Robins, E. Research diagnostic criteria for a selected group of functional disorders. (New York State Psychiatric Institute, 1978).
Gyapay, G. et al. The 1993–94 Généthon human genetic linkage map. Nature Genet. 7, 246–339 (1994).
Spielman, R.S., McGinnis, R.E. & Ewens, W.J. Transmission test for linkage disequilibrium: The insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am. J. hum. Genet. 52, 506–516 (1993).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Moises, H., Yang, L., Kristbjarnarson, H. et al. An international two–stage genome–wide search for schizophrenia susceptibility genes. Nat Genet 11, 321–324 (1995). https://doi.org/10.1038/ng1195-321
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/ng1195-321
This article is cited by
-
Schizophrenia in the genetic era: a review from development history, clinical features and genomic research approaches to insights of susceptibility genes
Metabolic Brain Disease (2023)
-
The Impact of Genes on Adolescent Substance Use: a Developmental Perspective
Current Addiction Reports (2019)
-
Functional genomics indicate that schizophrenia may be an adult vascular-ischemic disorder
Translational Psychiatry (2015)
-
Risk of Becoming Schizophrenic: Birth Order and HLA Profile
Proceedings of the Zoological Society (2013)
-
A polymorphism in the dysbindin gene (DTNBP1) associated with multiple psychiatric disorders including schizophrenia
Behavioral and Brain Functions (2010)
