A GWAS SNP for Schizophrenia Is Linked to the Internal MIR137 Promoter and Supports Differential Allele-Specific Expression

Alix Warburton,Vivien J Bubb,John P Quinn,Gerome Breen

doi:10.1093/schbul/sbv144

Abstract

Single nucleotide polymorphisms (SNPs) within the MIR137 gene locus have been shown to confer risk for schizophrenia through genome-wide association studies (GWAS). The expression levels of microRNA-137 (miR-137) and its validated gene targets have also been shown to be disrupted in several neuropsychiatric conditions, including schizophrenia. Regulation of miR-137 expression is thus imperative for normal neuronal functioning. We previously characterized an internal promoter domain within the MIR137 gene that contained a variable number tandem repeat (VNTR) polymorphism and could alter the in vitro levels of miR-137 in a stimulus-induced and allele-specific manner. We now demonstrate that haplotype tagging-SNP analysis linked the rs1625579 GWAS SNP for schizophrenia to this internal MIR137 promoter through a proxy SNP rs2660304 located at this domain. We postulated that the rs2660304 promoter SNP may act as predisposing factor for schizophrenia through altering the levels of miR-137 expression in a genotype-dependent manner. Reporter gene analysis of the internal MIR137 promoter containing the common VNTR variant demonstrated genotype-dependent differences in promoter activity with respect to rs2660304. In line with previous reports, the major allele of the rs2660304 proxy SNP, which has previously been linked with schizophrenia risk through genetic association, resulted in downregulation of reporter gene expression in a tissue culture model. The genetic influence of the rs2660304 proxy SNP on the transcriptional activity of the internal MIR137 promoter, and thus the levels of miR-137 expression, therefore offers a distinct regulatory mechanism to explain the functional significance of the rs1625579 GWAS SNP for schizophrenia risk.

Highlights

The functional significance of the previously identified rs1625579 genome-wide association studies (GWAS) single nucleotide polymorphisms (SNPs) for schizophrenia located within the third intron of the MIR137 gene remains elusive
As previously reported the MIR137 variable number tandem repeat (VNTR) was not found to be in linkage disequilibrium (LD) with the GWAS SNP nor tagged by any other markers within the same haplotype blocks.[9]
The location of the associated SNPs within noncoding sequences suggests that the functional significance could be related to transcriptional or posttranscriptional regulation of the MIR137 gene

Summary

Introduction

We recently characterized an internal promoter within the MIR137 gene locus, which we termed Imir[137], and validated its potential to modulate the levels of miR-137 expression in vitro using a reporter gene system.[9] The Imir[137] promoter encompasses a variable number tandem repeat (VNTR) domain, which has previously been shown to modulate the processing and function of miR137 in melanoma cell lines.[10] We demonstrated the ability of this polymorphic domain to modify the transcriptional activity of the Imir[137] promoter in an allele-specific and stimulus-inducible manner.[9] Haplotype analysis of the MIR137 gene locus using genotype data from the HapMap CEU cohort showed that the MIR137 GWAS single nucleotide polymorphisms (SNPs) for schizophrenia were not in linkage disequilibrium (LD) with the MIR137 VNTR.[9] In this communication we show that the rs1625579 GWAS SNP does, tag the rs2660304 SNP located at the identified Imir[137] promoter. Both rs1625579 and the rs2660304 promoter SNP have been shown to modulate the levels of miR-137 expression.[11,12] In this manuscript we propose a mechanism by which rs2660304 modulates miR-137 levels

Methods

Results

Conclusion