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 micro satellite markers at an average inter-marker distance of 17.26 cM, Multipoi nt affected sib pair analysis identified seven regions with a maximum lod s core (MLS) at or above the level associated with a nominal pointwise signif icance 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 u naffected siblings. This allowed the regions identified in stage 1 to be ty ped at an average spacing of 5.15 cM, while the region of interest on chrom osome 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 si gnificance of 0.05. We obtained three multipoint MLSs >1.5 and, on this bas is, the results on chromosomes 4p, 18q and Xcen can be considered suggestiv e. However, none approached a genome-wide significance of 0.05. The power o f this study was >0.95 to detect a susceptibility locus of lambda(s) = 3 wi th a genome-wide significance of 0.05, but only 0.70 to detect a locus of l ambda(s) = 2. Our results suggest that common genes of major effect (lambda (s) > 3) are unlikely to exist for schizophrenia.