Genetic heterogeneity in schizophrenia: stratification of genome scan datausing co-segregating related phenotypes

Despite considerable effort to identify susceptibility loci for schizophren ia, none have been localized. Multiple genome scans and collaborative effor ts have shown evidence for linkage to regions on chromosomes 1q, 5q, 6q, 8p , 13q, 10p and 22q.(1-9) Heterogeneity is likely, We previously mapped schi zophrenia susceptibility loci (SSL) to chromosomes 13q32 (P = 0.00002) and 8p21-22 (P = 0.0001) using 54 multiplex pedigrees and suggested linkage het erogeneity. We have now stratified these families based on cc-segregating p henotypes in nonschizophrenic first degree relatives (schizophrenia spectru m personality disorders (SSPD); psychotic affective disorders (PAD)). Genom e scans were conducted for these phenotypic subgroups of families and broad ened affected phenotypes were tested. The SSPD group provided its strongest genome-wide linkage support far the chromosome 8p21 region (D8S1771) using either narrow (non-parametric [od (NPL) P = 0.000002) or broadened phenoty pes (NPL P = 0.0000008) and a new region of interest on Ip was identified ( P = 0.006). For PAD families, the peak NPL in the genome scan occurred on c hromosome 3p26-p24 (P = 0.008). The identification of multiple susceptibili ty loci for schizophrenia may be enhanced by stratification of families usi ng psychiatric diagnoses of the non-schizophrenic relatives.