Multigenic inheritance of schizophrenia: A genome scan identifies susceptibility loci on chromosomes 13q32 and 8p21

Schizophrenia is a common "complex" phenotype with strong evidence of genetic susceptibility. A genome-wide scan for schizophrenia susceptibility loci (SSL) has been completed in a sample of 54 multiplex families, the majority of which were from the Maryland Epidemiologic Sample (MES). Genotypes at 452 highly polymorphic markers at an average interval of 7.6 cM were obtained for 363 individuals. Nonparametric linkage analysis provided significant evidence for an SSL on chromosome 13q32 near marker D13S174 (NPL score 4.18; P value 0.00002) and suggestive evidence for another SSL on chromosome 8p21-22 near marker D8S1771 (NPL score 3.64; P value 0.00001). Parametric linkage analysis provided additional evidence for the existence of these SSLs. Additional putative SSLs were noted on chromosomes 14q13 (NPL score 2.57; P = 0.005), 7q11 (NPL score 2.50; P = 0.007), 22q11 (NPL score 2.42; P = 0.009) near D14S306, D7S2212, and D22S1265, respectively. To verify the suggestive SSLs on chromosomes 13q and 8p, we performed nonparametric analysis using a replication sample of 51 multiplex pedigrees. This analysis also supported the SSLs in 13q14-q33 (NPL = 2.36, P = .007) and 8p22-p21 (NPL = 1.95, P = .023). Heterogeneity analyses suggested differential contributions to identified regions based on family characteristics. The cloning of these SSL genes and the study of mutations associated with the phenotype will greatly enhance our understanding of the molecular pathogenesis of this disease.