A multimodal attempt to follow-up linkage regions using RNA expression, SNPs and CpG methylation in schizophrenia and bipolar disorder kindreds

Abstract

The complexity of schizophrenia (SZ) and bipolar disorder (BD) has slowed down progress in understanding their genetic roots. Alternative genomic approaches are needed to bypass these difficulties. We attempted a multimodal approach to follow-up on reported linkage findings in SZ and BD from the Eastern Quebec kindreds in chromosomes 3q21, 4p34, 6p22, 8p21, 8p11, 13q11-q14, 15q13, 16p12, and 18q21. First, in 498 subjects, we measured RNA expression (47 K Illumina chips) in SZ and BD patients that we compared with their non-affected relatives (NARs) to identify, for each chromosomal region, genes showing the most significant differences in expression. Second, we performed SNP genotyping (700 K Illumina chips) and cis-eQTN analysis. Third, we measured DNA methylation on genes with RNA expression differences or eQTNs. We found a significant overexpression of the gene ITGB5 at 3q25 in SZ and BD after multiple testing p value adjustment. SPCS3 gene at 4q34, and FZD3 gene at 8p21, contained significant eQTNs after multiple testing corrections, while ITGB5 provided suggestive results. Methylation in associated genes did not explain the expression differences between patients and NARs. Our multimodal approach involving RNA expression, dense SNP genotyping and eQTN analyses, restricted to chromosomal regions having shown linkage, lowered the multiple testing burden and allowed for a deeper examination of candidate genes in SZ or BD.