| Abstract |
Genome-wide association studies (GWAS) in精神分裂症have focused on additive allelic effects to identify disease risk loci. In order to examine potential recessive effects, we applied a novel approach to identify regions of excess homozygosity in an ethnically homogenous cohort: 904精神分裂症cases and 1640 controls drawn from the Ashkenazi Jewish (AJ) population. Genome-wide examination of runs of homozygosity identified an excess in cases localized to the major histocompatibility complex (MHC). To refine this signal, we used the recently developed GERMLINE algorithm to identify chromosomal segments shared identical-by-descent (IBD) and compared homozygosity at such segments in cases and controls. We found a significant excess of homozygosity in精神分裂症cases compared with controls in the MHC (P-value = 0.003). An independent replication cohort of 548精神分裂症cases from Japan and 542 matched healthy controls demonstrated similar effects. The strongest case-control recessive effects (P = 8.81 � 10(-8)) were localized to a 53-kb region near HLA-A, in a segment encompassing three poorly annotated genes,TRIM10, TRIM15 and TRIM40. At the same time, an adjacent segment in the Class I MHC demonstrated clear additive effects on精神分裂症risk, demonstrating the complexity of association in the MHC and the ability of our IBD approach to refine localization of broad signals derived from conventional GWAS. In sum, homozygosity in the classical MHC region appears to convey significant risk for精神分裂症, consistent with the ecological literature suggesting that homozygosity at the MHC locus may be associated with vulnerability to disease. |