The missing link between genetic association and regulatory function

Abstract

The genetic basis of most complex traits is highly polygenic and dominated by non-coding alleles. It is widely assumed that such alleles exert small regulatory effects on the expression of cis-linked genes. However, despite the availability of expansive gene expression and epigenomic data sets, few variant-to-gene links have emerged. We identified 134 gene-trait pairs in which protein-coding variants cause severe or familial forms of nine human traits. For most of these genes, we find that adjacent non-coding variation is associated with common complex forms of the same traits. However, we found limited evidence of colocalization—the same variant influencing both the physiological trait and gene expression—for only 7% of genes, and transcriptome-wide association evidence with correct direction of effect for only 6% of genes, despite the presence of eQTLs in most loci. Fine-mapping variants to regulatory elements and assigning these to genes by linear distance similarly failed to implicate most genes in complex traits. These results contradict the hypothesis that most complex trait-associated variants coincide with currently ascertained expression quantitative trait loci. The field must confront this deficit, and pursue this “missing regulation.”