Polymorphisms in microRNA target sites influence susceptibility to schizophrenia by altering the binding of miRNAs to their targets

Abstract

Single nucleotide polymorphisms (SNPs) in 3' untranslated regions (3' UTRs) of genes may affect miRNA binding to messenger RNA and contribute to the risk of disease. Whether the SNPs that modify miRNA binding in the 3' UTR are involved in schizophrenia-related genes remains unclear. We selected 803 SNPs from the 3' UTRs of 425 candidate genes for schizophrenia. The potential target SNPs were recognized by Gibbs free energy of miRNA binding. Some SNPs were associated in the literature with schizophrenia or other related neurological diseases. A case-control study of nine SNPs not previously reported as significant in any disease was carried out in a Chinese-Han cohort. We found that rs3219151 (C>T, GABRA6) showed significant decreased risk for schizophrenia (OR=0.8121, p=0.008, p(adjust)=0.03). Further, two putative target SNPs, rs165599 (COMT) and rs10759 (RGS4) reported in several references previously, were selected for analysis by luciferase assay to determine their modification to miRNA binding. We found that miR-124 showed significantly repressed 3' UTR binding to RGS4 mRNA from the rs10759-C allele (p<0.05). Our results suggest that rs3219151 of GABRA6 was associated significantly to decrease the risk of schizophrenia, rs10759 (RGS4) was possible to increase the risk of schizophrenia by miRNA altering the binding of miRNAs to their targets influencing susceptibility to schizophrenia.

Keywords: 3′ untranslated regions (3′ UTRs); Binding site; SNP; Schizophrenia; miRNA.