Genetic association of molecular traits: A help to identify causative variants in complex diseases

Abstract

In the past 15 years, major progresses have been made in the understanding of the genetic basis of regulation of gene expression. These new insights have revolutionized our approach to resolve the genetic variation underlying complex diseases. Gene transcript levels were the first expression phenotypes that were studied. They are heritable and therefore amenable to genome-wide association studies. The genetic variants that modulate them are called expression quantitative trait loci. Their study has been extended to other molecular quantitative trait loci (molQTLs) that regulate gene expression at the various levels, from chromatin state to cellular responses. Altogether, these studies have generated a wealth of basic information on the genome-wide patterns of gene expression and their inter-individual variation. Most importantly, molQTLs have become an invaluable asset in the genetic study of complex diseases. Although the identification of the disease-causing variants on the basis of their overlap with molQTLs requires caution, molQTLs can help to prioritize the relevant candidate gene(s) in the disease-associated regions and bring a functional interpretation of the associated variants, therefore, bridging the gap between genotypes and clinical phenotypes.

Keywords: GWAS; causative variants; complex disease; eQTL; fine-mapping; linkage disequilibrium; molQTL; molecular trait; quantitative trait.