Chemical Genetic Validation of GWAS-derived Disease Loci

Background: Genome-wide association studies (GWAS) have opened the door to unprecedented large-scale identification of susceptibility loci for human diseases and traits. However, it is still a great challenge to validate these loci and elucidate how these sequence variants give rise to the genetic and phenotypic changes. Because many drug targets are genetic disease genes and the general drug mode of action (MoA, agonist or antagonist) is in line with the consequence of target gene mutations (loss-of-function (LOF) or gain-of-function (GOF)), here we propose a chemical genetic method to address the above issues of GWAS. Objective: This study intends to use chemical genetics information to validate GWAS-derived disease loci and interpret their underlying pathogenesis. Methods: We conducted a comprehensive comparative analysis on GWAS data and drug/target information (chemical genetics information). Results: We have identified hundreds of GWAS-derived disease loci which are linked to drug target genes and have matched disease traits and drug indications. It is interesting to note that more than 40% genes have been recognized as disorder factors, indicating the potential power of chemical genetic validation. The pathogenesis of these loci was inferred by the corresponding drug MoA. Some inferences were supported by prior experimental observations; some were interpreted in terms of microRNA regulation, codon usage bias, and transcriptional regulation, in particular the transcription factor-binding affinity variation induced by disease-causing mutations. Conclusion: In summary, chemical genetics information is useful to validate GWAS-derived disease loci and to interpret their underlying pathogenesis as well, which has important implications not only in medical genetics but also in methodology evaluation of GWAS.

Automated summary

Utilizing chemical genetics information to validate GWAS-derived disease loci and interpret their underlying pathogenesis through comparative analysis, this study identified numerous loci associated with drug target genes, disease traits, and drug indications. More than 40% of genes were recognized as disorder factors, highlighting the potential power of chemical genetic validation. Inferences about the pathogenesis of these loci were made based on the corresponding drug mode of action, suggesting important implications for not only medical genetics but also the evaluation of GWAS methodology.