A schizophrenia-susceptibility locus at 6q25, in one of the world's largest reported pedigrees

We have completed a genome scan of a 12-generation, 3,400-member pedigree w ith schizophrenia. Samples from 210 individuals were collected from the ped igree. We performed an "affecteds-only" genome-scan analysis using 43 membe rs of the pedigree. The affected individuals included 29 patients with schi zophrenia, 10 with schizoaffective disorders, and 4 with psychosis not othe rwise specified. Two sets of white-European allele frequencies were used-on e from a Swedish control population (46 unrelated individuals) and one from the pedigree (210 individuals). All analyses pointed to the same region: D 6S264, located at 6q25.2, showed a maximum LOD score of 3.45 when allele fr equencies in the Swedish control population were used, compared with a maxi mum LOD score of 2.59 when the pedigree's allele frequencies were used. We analyzed additional markers in the 6q25 region and found a maximum LOD scor e of 6.6 with marker D6S253, as well as a 6-cM haplotype (markers D6S253-D6 S264) that segregated, after 12 generations, with the majority of the affec ted individuals. Multipoint analysis was performed with the markers in the 6q25 region, and a maximum LOD score of 7.7 was obtained. To evaluate the s ignificance of the genome scan, we simulated the complete analysis under th e assumption of no linkage. The results showed that a LOD score > 2.2 shoul d be considered as suggestive of linkage, whereas a LOD score > 3.7 should be considered as significant. These results suggest that a common ancestral region was inherited by the affected individuals in this large pedigree.