Lessons from Functional Analysis of Genome-Wide Association Studies

Abstract

Most cancer-associated single-nucleotide polymorphisms (SNP) identified using genome-wide association studies are located outside of protein-coding regions, and their significance and mode of action have been a source of continuing debate. One proposed mechanism of action of the SNPs is that they would affect the activity of enhancer elements regulating critical target genes. In this review, we summarize recent results that substantiate this model. These studies have identified a cancer-specific enhancer element at the 8q24 gene desert that controls the expression of the MYC oncogene. We further discuss implications of the observed difference between normal growth control and cancer for drug development, and the inherent features of genome-wide association studies that may specifically lead to identification of disease-specific regulatory elements.

Common cancers share familial susceptibility: implications for cancer genetics and counselling

“…A number of tumour suppressor genes are involved in DNA repair, guarding the integrity of the genome, or in other essential cellular processes, and it would be easily understandable that damage in such genes would promote cancers in many tissues; these processes have been coined as ‘hallmarks of cancer’ 18–21. Furthermore, GWASs have identified genomic locations which contribute to susceptibility of numerous cancers, including chromosome 8q24 next to the MYC gene and 5p next to the TERT gene 2 22 23. However, SNPs in these loci are largely specific to individual cancers but their clustering next to the important effector genes is thought to signal shared mechanisms.…”

The role of enhancers in cancer

“…To reach statistical significance, these studies require a large number of individual alleles, and thus they are biased towards identifying variants that are common in the population. Such common variants generally have a limited effect on fitness and viability, which indicates that the GWAS-identified enhancers and their target genes might be attractive targets of cancer chemoprevention and therapy 88 . The modest effect of risk alleles is also indicative of the robustness of the mechanisms that control normal growth and proliferation against minor perturbations in the transcriptional regulatory networks.…”

Genetic Variation Determines PPARγ Function and Anti-diabetic Drug Response In Vivo

“…The causal SNP for an LDL cholesterol and myocardial infarction locus is a regulatory variant altering hepatic SORT1 expression (Musunuru et al, 2010). Regulatory SNPs in distant enhancers for MYC result in associations with multiple cancers (Sur et al, 2013), and an intronic enhancer SNP in TCF7L2 may mediate type 2 diabetes (T2D) risk (Gaulton et al, 2010). For the PPARG T2D locus, the causal SNP was thought to be a coding Pro12Ala polymorphism, yet recent evidence has implicated a tightly linked regulatory SNP (Claussnitzer et al, 2014).…”