A genomic screen of autism: Evidence for a multilocus etiology

We have conducted a genome screen of autism, by linkage analysis in an init ial set of 90 multiplex sibships, with parents, containing 97 independent a ffected sib pairs (ASPs), with follow-up in 49 additional multiplex sibship s, containing 50 ASPs. In total, 519 markers were genotyped, including 362 for the initial screen, and an additional 157 were genotyped in the follow- up. As a control, we also included in the analysis unaffected sibs, which p rovided 51 discordant sib pairs (DSPs) for the initial screen and 29 for th e follow-up. In the initial phase of the work, we observed increased identi ty by descent (IBD) in the ASPs (sharing of 51.6%) compared with the DSPs ( sharing of 50.8%). The excess sharing in the ASPs could not be attributed t o the effect of a small number of loci but, rather, was due to the modest i ncrease in the entire distribution of IBD. These results are most compatibl e with a model specifying a large number of loci (perhaps greater than or e qual to 15) and are less compatible with models specifying less than or equ al to 10 loci. The largest LOD score obtained in the initial scan was for a marker on chromosome 1p; this region also showed positive sharing in the r eplication family set, giving a maximum multipoint LOD score of 2.15 for bo th sets combined. Thus, there may exist a gene of moderate effect in this r egion. We had only modestly positive or negative linkage evidence in candid ate regions identified in other studies. Our results suggest that positiona l cloning of susceptibility loci by linkage analysis may be a formidable ta sk and that other approaches may be necessary.