An international two–stage genome–wide search for schizophrenia susceptibility genes

Schizophrenia is thought to be a multifactorial disease with complex mode of inheritance^1,2. 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 findings^4,5 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.