Cis-SNPs Set Testing and PrediXcan Analysis for Gene Expression Data using Linear Mixed Models.

Understanding the functional mechanism of SNPs identified in GWAS on complex diseases is currently a challenging task. The studies of expression quantitative trait loci (eQTL) have shown that regulatory variants play a crucial role in the function of associated SNPs. Detecting significant genes (called eGenes) in eQTL studies and analyzing the effect sizes of cis-SNPs can offer important implications on the genetic architecture of associated SNPs and interpretations of the molecular basis of diseases. We applied linear mixed models (LMM) to the gene expression level and constructed likelihood ratio tests (LRT) to test for eGene in the Geuvadis data. We identified about 11% genes as eGenes in the Geuvadis data and found some eGenes were enriched in approximately independent linkage disequilibrium (LD) blocks (e.g. MHC). We further performed PrediXcan analysis for seven diseases in the WTCCC data with weights estimated using LMM and identified 64, 5, 21 and 1 significant genes (p < 0.05 after Bonferroni correction) associated with T1D, CD, RA and T2D. We found most of the significant genes of T1D and RA were also located within the MHC region. Our results provide strong evidence that gene expression plays an intermediate role for the associated variants in GWAS.