A two-stage genome scan for schizophrenia susceptibility genes in 196 affected sibling pairs

We undertook a systematic search for linkage in 196 affected sibling pairs (ASPs) with DSMIV schizophrenia. In stage 1 we typed 97 ASPs with 229 microsatellite markers at an average inter-marker distance of 17.26 cM. Multipoint affected sib pair analysis identified seven regions with a maximum lod score (MLS) at or above the level associated with a nominal pointwise significance of 5%, on chromosomes 2q, 4p, 10q, 15q, 18p, 20q and Xcen. In stage 2 we genotyped a further 54 markers in 196 ASPs together with parents and unaffected siblings. This allowed the regions identified in stage 1 to be typed at an average spacing of 5.15 cM, while the region of interest on chromosome 2 was typed to 9.55 cM. Analysis was performed on the whole data set. Simulation studies suggested that we would expect one multipoint MLS of 1.5 per genome scan in the absence of linkage. An MLS of 3 would be expected only once in every 20 genome scans and thus corresponds to a genome-wide significance of 0.05. We obtained three multipoint MLSs > 1.5 and, on this basis, the results on chromosomes 4p, 18q and Xcen can be considered suggestive. However, none approached a genome-wide significance of 0.05. The power of this study was > 0.95 to detect a susceptibility locus of λ(s) = 3 with a genome-wide significance of 0.05, but only 0.70 to detect a locus of λ(s) = 2. Our results suggest that common genes of major effect (λ(s) > 3) are unlikely to exist for schizophrenia.