Genome-wide association study identifies chromosome 10q24.32 variants associated with arsenic metabolism and toxicity phenotypes in Bangladesh

Abstract

Arsenic contamination of drinking water is a major public health issue in many countries, increasing risk for a wide array of diseases, including cancer. There is inter-individual variation in arsenic metabolism efficiency and susceptibility to arsenic toxicity; however, the basis of this variation is not well understood. Here, we have performed the first genome-wide association study (GWAS) of arsenic-related metabolism and toxicity phenotypes to improve our understanding of the mechanisms by which arsenic affects health. Using data on urinary arsenic metabolite concentrations and approximately 300,000 genome-wide single nucleotide polymorphisms (SNPs) for 1,313 arsenic-exposed Bangladeshi individuals, we identified genome-wide significant association signals (P<5×10(-8)) for percentages of both monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) near the AS3MT gene (arsenite methyltransferase; 10q24.32), with five genetic variants showing independent associations. In a follow-up analysis of 1,085 individuals with arsenic-induced premalignant skin lesions (the classical sign of arsenic toxicity) and 1,794 controls, we show that one of these five variants (rs9527) is also associated with skin lesion risk (P = 0.0005). Using a subset of individuals with prospectively measured arsenic (n = 769), we show that rs9527 interacts with arsenic to influence incident skin lesion risk (P = 0.01). Expression quantitative trait locus (eQTL) analyses of genome-wide expression data from 950 individual's lymphocyte RNA suggest that several of our lead SNPs represent cis-eQTLs for AS3MT (P = 10(-12)) and neighboring gene C10orf32 (P = 10(-44)), which are involved in C10orf32-AS3MT read-through transcription. This is the largest and most comprehensive genomic investigation of arsenic metabolism and toxicity to date, the only GWAS of any arsenic-related trait, and the first study to implicate 10q24.32 variants in both arsenic metabolism and arsenical skin lesion risk. The observed patterns of associations suggest that MMA% and DMA% have distinct genetic determinants and support the hypothesis that DMA is the less toxic of these two methylated arsenic species. These results have potential translational implications for the prevention and treatment of arsenic-associated toxicities worldwide.

Figure 1. Multiple variants in the 10q24.32 region show independent associations with DMA% (n = 1,313).

P-values were generated using mixed models adjusted for age, sex, and water arsenic concentration. The strongest associated SNP is labeled in each panel. Panel A shows the overall association results. Panel B shows P-values from models that are adjusted for rs9527. Panel C shows P-values from models adjusted for both rs9527 and rs11191527.

Figure 2. Multiple variants in the 10q24.32 region show independent associations with MMA% (n = 1,313).

P-values were generated using mixed models adjusted for age, sex, and water arsenic concentration. The strongest associated SNP is labeled in each panel. Panel A shows the overall association results. Panel B shows P-values from models that are adjusted for rs4919694. Panel C shows P-values from models adjusted for both rs4919694 and rs4290163.

Figure 3. Variants in the 10q24.32 region are associated with transcript levels of AS3MT and C10orf32.

C10orf32 is ∼4 kb from AS3MT and involved in C10orf32-AS3MT read-through transcription. P-values were generated using mixed linear models adjusted for age and sex.