Chemotherapeutic drug susceptibility associated SNPs are enriched in expression quantitative trait loci

Abstract

Pharmacogenomics has employed candidate gene studies and, more recently, genome-wide association studies (GWAS) in efforts to identify loci associated with drug response and/or toxicity. The advantage of GWAS is the simultaneous, unbiased testing of millions of SNPs; the challenge is that functional information is absent for the vast majority of loci that are implicated. In the present study, we systematically evaluated SNPs associated with chemotherapeutic agent-induced cytotoxicity for six different anticancer agents and evaluated whether these SNPs were disproportionately likely to be within a functional class such as coding (consisting of missense, nonsense, or frameshift polymorphisms), noncoding (such as 3′UTRs or splice sites), or expression quantitative trait loci (eQTLs; indicating that a SNP genotype is associated with the transcript abundance level of a gene). We found that the chemotherapeutic drug susceptibility-associated SNPs are more likely to be eQTLs, and, in fact, more likely to be associated with the transcriptional expression level of multiple genes (n ≥ 10) as potential master regulators, than a random set of SNPs in the genome, conditional on minor allele frequency. Furthermore, we observed that this enrichment compared with random expectation is not present for other traditionally important coding and noncoding SNP functional categories. This research therefore has significant implications as a general approach for the identification of genetic predictors of drug response and provides important insights into the likely function of SNPs identified in GWAS analysis of pharmacologic studies.genome-wide association study | pharmacogenomics

Genome-wide association study of obsessive-compulsive disorder

“…37 This model-free approach to gene discovery has led to a greater pathophysiologic understanding of many disorders, although only small proportions of the total genetic variance have so far been explained, and many of the identified variants have not brought new biological understanding. 38 To address the latter concern, functional support for GWAS findings has been sought by determining their effects on gene expression (expression quantitative trait loci- eQTLs) and methylation level (methylation quantitative trait loci-mQTLs). 38 Top single nucleotide polymorphisms (SNPs) have also been examined for potential enrichment of eQTLs and mQTLs, compared to expected rates.…”

“…38 To address the latter concern, functional support for GWAS findings has been sought by determining their effects on gene expression (expression quantitative trait loci- eQTLs) and methylation level (methylation quantitative trait loci-mQTLs). 38 Top single nucleotide polymorphisms (SNPs) have also been examined for potential enrichment of eQTLs and mQTLs, compared to expected rates. Moreover, examination for over-representation of micro-RNA (miRNA) binding sites has also been adopted as an informative approach, 39 given the role of miRNA in regulating gene expression.…”

Functional genetic screen of human diversity reveals that a methionine salvage enzyme regulates inflammatory cell death

“…Thus, although there was no evidence of systematic bias, there were no SNPs with P values lower than neutral expectation. However, previous work has shown the value in examining functional subsets of SNPs, specifically SNPs associated with expression levels of nearby genes [cis-expression quantitative trait loci (cis-eQTL)], to enhance discovery from GWAS (26)(27)(28). Doing so also makes biological sense, because SNPs that alter nearby gene expression are more likely to affect cellular function as well.…”

Consensus Genome-Wide Expression Quantitative Trait Loci and Their Relationship with Human Complex Trait Disease

“…Several studies have shown that SNPs associated with human traits and chemotherapeutic drug susceptibility are in general enriched for eQTLs (Cookson et al, 2009;Gamazon et al, 2010;Nicolae et al, 2010). Most studies have used eQTL data from the most accessible cell type, LCL, and it is not clear how good a proxy these are for human cells and tissues relevant to nonimmune-related disease, such as psychiatric traits or cancers (Choy et al, 2008;Nicolae et al, 2010).…”