Identification of a functional SNP rs7304782 at schizophrenia risk locus 12q24.31 and validation of its association with schiz ophrenia in Chinese populations

Abstract

Recent genome-wide association studies (GWAS) have identified multiple schizophrenia-associated risk loci. However, the potential functional (or causal) variant remains largely unknown for each of the identified risk locus. In this study, we utilized different functional annotation approaches (i.e., CADD, Eigen, GWAVA, RegulomeDB and LINSIGHT) to prioritize the most possible functional variant at schizophrenia risk locus 12q24.31, a risk locus that showed genome-wide significant association with schizophrenia. We found that four functional annotation methods prioritized rs7304782 as a potential functional variant at 12q24.31, suggesting the potential functional consequence of rs7304782. Consistent with the functional annotation, reporter gene assays showed that different allele of rs7304782 affected the luciferase activity significantly, further supporting that rs7304782 is a functional variant. We further performed genetic association study and validated that rs7304782 is also associated with schizophrenia in Chinese population (N=4,291 cases and 7,847 controls), with the same risk allele as in European population. Expression quantitative trait loci (eQTL) analysis indicated that rs7304782 was significantly associated with the expression of OGFOD2 in human brain tissues. Of note, differential expression analysis indicated that OGFOD2 was significantly down-regulated in schizophrenia cases compared with controls. Our study identified a potential functional variant (i.e., rs7304782) at schizophrenia risk locus 12q24.31 and suggested that this functional variant may confer schizophrenia risk through regulating OGFOD2 expression.