Multivariate eQTL mapping uncovers functional variation on the X-chromosome associated with complex disease traits.

Very few studies have investigated the associations between genetic polymorphisms and gene expression on the X-chromosome. This is a major bottleneck when conducting functional follow-up studies of trait-associated variants, as those identified in genome-wide association studies (GWAS). We used a multivariate approach to test the association between individual single nucleotide polymorphisms (SNPs) and exon expression levels measured in 356 Epstein-Barr virus-transformed lymphoblastoid cell lines (LCLs) from the Geuvadis RNA sequencing project to identify SNPs associated with variation in gene expression on the X-chromosome, which we refer to as eSNPs. At an FDR of 5 %, we discovered 548 independent [linkage disequilibrium (LD) r (2) < 0.1] eSNPs on the X-chromosome. Of these, 35 were in LD (r (2) > 0.8) with previously published disease- or trait-associated variants identified through GWAS. One of the strongest eSNPs identified was rs35975601, which was associated with F8A1 expression (p value = 3 × 10(-20)) and was in LD with a type 1 diabetes risk variant. Additionally, we identified a number of genes for which eSNPs were in LD with multiple diseases or traits, including DNASE1L1 which was mapped to bilirubin levels, type 1 diabetes and schizophrenia. Our results also indicate that multivariate exon-level analysis provides a more powerful approach than univariate gene-level analysis, particularly when SNPs influence the expression of different exons with different magnitude and/or direction of effect. The associations identified in our study may provide new insights into the molecular process by which gene expression may contribute to trait variation or disease risk in humans.