Genome-Wide Haplotype Analysis of Cis Expression Quantitative Trait Loci in Monocytes

Abstract In order to assess whether gene expression variability could be influenced by several SNPs acting in cis, either throughadditive or more complex haplotype effects, a systematic genome-wide search for cis haplotype expression quantitativetrait loci (eQTL) was conducted in a sample of 758 individuals, part of the Cardiogenics Transcriptomic Study, for whichgenome-wide monocyte expression and GWAS data were available. 19,805 RNA probes were assessed for cis haplotypicregulation through investigation of ,2,1610 9 haplotypic combinations. 2,650 probes demonstrated haplotypic p-values .10 4 -fold smaller than the best single SNP p-value. Replication of significant haplotype effects were tested for 412probes for which SNPs (or proxies) that defined the detected haplotypes were available in the Gutenberg Health Studycomposed of 1,374 individuals. At the Bonferroni correction level of 1.2610 24 (,0.05/412), 193 haplotypic signalsreplicated. 1000G imputation was then conducted, and 105 haplotypic signals still remained more informative than imputedSNPs. In-depth analysis of these 105 cis eQTL revealed that at 76 loci genetic associations were compatible with additiveeffects of several SNPs, while for the 29 remaining regions data could be compatible with a more complex haplotypicpattern. As 24 of the 105 cis eQTL have previously been reported to be disease-associated loci, this work highlights the needfor conducting haplotype-based and 1000G imputed cis eQTL analysis before commencing functional studies at disease-associated loci.