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.