Profiling haplotype specific CpG and CpH methylation within a schizophrenia GWAS locus on chromosome 14 in schizophrenia and healthy subjects

Abstract

AbstractInterrogating DNA methylation within schizophrenia risk loci holds promise to identify mechanisms by which genes influence the disease. Based on the hypothesis that allele specific methylation (ASM) of a single CpG, or perhaps CpH, might mediate or mark the effects of genetic variants on disease risk and phenotypes, we explored haplotype specific methylation levels of individual cytosines within a genomic region harbouring the BAG5, APOPT1 and KLC1 genes in peripheral blood of schizophrenia patients and healthy controls. Three DNA fragments located in promoter, intronic and intergenic areas were studied by single-molecule real-time bisulfite sequencing enabling the analysis of long reads of DNA with base-pair resolution and the determination of haplotypes directly from sequencing data. Among 1,012 cytosines studied, we did not find any site where methylation correlated with the disease or cognitive deficits after correction for multiple testing. At the same time, we determined the methylation profile associated with the schizophrenia risk haplotype within the KLC1 fourth intron and confirmed ASM for cytosines located in the vicinity of rs67899457. These genetically associated DNA methylation variations may be related to the pathophysiological mechanism differentiating the risk and non-risk haplotypes and merit further investigation.