Schizophrenia is a common disorder characterized by psychotic symptoms; diagnostic criteria have been established1. Family, twin and adoption studies suggest that both genetic and environmental factors influence susceptibility (heritability is approximately 71%; ref. 2), however, little is known about the aetiology of schizophrenia. Clinical and family studies suggest aetiological heterogeneity3,6. Previously, we reported that regions on chromosomes 22, 3 and 8 may be associated with susceptibility to schizophrenia7,8, and collaborations provided some support for regions on chromosomes 8 and 22 (refs 9, 10, 11, 12, 13). We present here a genome-wide scan for schizophrenia susceptibility loci (SSL) using 452 microsatellite markers on 54 multiplex pedigrees. Non-parametric linkage (NPL) analysis provided significant evidence for an SSL on chromosome 13q32 (NPL score = 4.18; P = 0.00002), and suggestive evidence for another SSL on chromosome 8p21–22 (NPL = 3.64; P = 0.0001). Parametric linkage analysis provided additional support for these SSL. Linkage evidence at chromosome 8 is weaker than that at chromosome 13, so it is more probable that chromosome 8 may be a false positive linkage. Additional putative SSL were noted on chromosomes 14q13 (NPL = 2.57; P = 0.005), 7q11 (NPL = 2.50, P = 0.007) and 22q11 (NPL = 2.42, P = 0.009). Verification of suggestive SSL on chromosomes 13q and 8p was attempted in a follow-up sample of 51 multiplex pedigrees. This analysis confirmed the SSL in 13q14-q33 (NPL = 2.36, P = 0.007) and supported the SSL in 8p22-p21 (NPL = 1.95, P = 0.023).
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American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, Washington D.C., 1994).
Rao, D.C., Morton, D.E., Gottesman, I.I. & Lew, R. Path analysis of qualitative data on pairs of relatives: Application to schizophrenia. Hum. Hered. 31, 325–333 (1981).
Tsuang, M.T. & Faraone, S.V. The case for heterogeneity in the etiology of schizophrenia. Schizophr. Res. 17, 161–175 (1995).
Pulver, A.E. & Liang, K.Y. Estimating effects of probands' characteristics on familial risk: II. The association between age at onset and familial risk in the Maryland schizophrenic sample. Genet. Epidemiol. 8, 339–350 ( 1991).
Pulver, A.E. et al. Risk factors in schizophrenia: season of birth, gender and familial risk. Br. J. Psychiatry 160, 65 –71 (1992).
Melton, B., Liang, K.Y. & Pulver, A.E. An extended latent class approach to the study of familial/sporadic forms of disease: Its application to the study of the heterogeneity of schizophrenia. Genet. Epidemiol. 11, 311–327 (1994).
Pulver, A.E. et al. Sequential strategy to identify a susceptibility gene for schizophrenia: Report of potential linkage on chromosome 22q12-q13.1: Part 1. Am. J. Med. Genet. 54, 36– 43 (1994).
Pulver, A.E. et al. Schizophrenia: A genome scan targets chromosomes 3p and 8p as potential sites of susceptibility genes. Am. J. Med. Genet. 60, 252–260 ( 1995).
Pulver, A.E. et al. Psychotic illness in patients diagnosed with velo-cardio-facial syndrome and their relatives. J. Nerv. Ment. Dis. 182 , 476–478 (1994).
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).
Gill, M. et al. A combined analysis of D22S278 marker alleles in affected sib-pairs: Support for a susceptibility locus for schizophrenia at chromosome 22q12. Am. J. Med Genet. 67, 40– 45 (1996).
Schizophrenia Linkage Collaborative Group for Chromosomes 3, 6 and 8; A Multicenter Study. Additional support for schizophrenia linkage on chromosome 6 and 8. Am. J. Med. Genet. 67, 580–594 (1996).
Kendler, K.S. et al. Evidence for a schizophrenia vulnerability locus on chromosome 8p in the Irish study of high-density schizophrenia families. Am. J. Psychiatry 153, 1534–1540 (1996).
Lander, E. & Kruglyak, L. (1995) Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nature Genet. 11, 241–247.
Straub, R.E. et al. A potential vulnerability locus for schizophrenia on chromosome 6p24-p22: Evidence for genetic heterogeneity. Nature Genet. 11, 287–293 (1995).
Freedman, R. et al. Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus. Proc. Natl Acad. Sci. USA 94 , 587–592 (1997).
Straub, R.E., MacLean, C.J., O'Neill, F.A., Walsh, D. & Kendler, K.S. Support for a possible schizophrenia vulnerability locus in region 5q22-31 in Irish families. Mol. Psychiatry 2, 148–155 ( 1997).
Wildenauer, D.B. et al. Searching for susceptibility genes in schizophrenia by genetic linkage analysis. Cold Spring Harb. Symp. Quant. Biol. 61, 845–850 (1996).
Antonarakis, S.E. et al. Schizophrenia susceptibility and chromosome 6p24-p22. Nature Genet. 11, 235–236 (1995).
Antonarakis, S.E. et al. Lack of linkage or association between schizophrenia and the polymorphic trinucleotide repeat within the KCNN3 gene on chromosome 1q21. Am. J. Med.Genet. in press.
Lin, M.W. et al. Suggestive evidence for linkage of schizophrenia to markers on chromosome 13q14.1-q32. Psychiatr. Genet. 5, 117–126 (1995).
Lin, M.W. et al. Suggestive evidence for linkage of schizophrenia to markers on chromosome 13 in Caucasian but not Oriental populations. Hum. Genet. 99, 417–420 ( 1997).
Pulver, A.E. et al. The Johns Hopkins University Schizophrenia Study: An epidemiologic-genetic approach to test the heterogeneity hypothesis and identify schizophrenia susceptibility genes. Cold Spring Harb. Symp. Quant. Biol. 61, 797–814 (1996).
Pulver, A.E. & Bale, S.J. Availabilty of schizophranic patients and their families for genetic linkage studies: Findings from the Maryland epidemiology study. Genet. Epidemiol. 6, 671–680 (1989).
Lasher, L., Refer, J. & Chakravarti, A. Effects of genotyping error on the estimation of chromosome map length. Am. J. Hum. Genet. 49, 369 (1991).
Buetow, K. H. Influence of aberrant observations on high-resolution linkage analysis outcomes. Am. J. Hum. Genet. 49, 985– 994 (1991).
Dausset, J. et al. Centre d'etude du polymorphisme humain (CEPH): collaborative genetic mapping of the human genome. Genomics 6, 575–577 (1990).
Matise, T.C., Perlin, M. & Chakravarti, A. Automated construction of genetic linkage maps using an expert system (Multimap): a human genome linkage map. Nature Genet. 6, 384–390 ( 1994).
Kruglyak, L., Daly, M.J., Reeve-Daly, M.P. & Lander, E.S. Parametric and nonparametric linkage analysis: A unified multipoint approach. Am. J. Hum. Genet. 58, 1347– 1363 (1996).
Conneally, P.M. et al. Report of the committee on methods of linkage analysis and reporting. Cytogenet. Cell Genet. 40, 356 –359 (1985).
This work was supported by funding from Novartis Pharmaceuticals (1995-1998), grants from the National Institutes of Mental Health (NIMH; 1989-1995; R01 MH-45588 and 1 R01 35712), the National Institutes of Health (NIH) grant DRR-OPD-GCRC RR00722, the National Alliance for Research on Schizophrenia and Depression and gifts from private foundations and private donors. We wish to thank the patients and their families and the mental health professionals who referred patients and provided information.
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