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. 2015 Oct;123(10):985-92.
doi: 10.1289/ehp.1408909. Epub 2015 Mar 13.

The Genetic Architecture of Arsenic Metabolism Efficiency:A SNP-Based Heritability Study of Bangladeshi Adults

Jianjun Gao  1 , Lin Tong, Maria Argos, Molly Scannell Bryan, Alauddin Ahmed, Muhammad Rakibuz-Zaman, Muhammad G Kibriya, Farzana Jasmine, Vesna Slavkovich, Joseph H Graziano, Habibul Ahsan, Brandon L Pierce
Affiliations

The Genetic Architecture of Arsenic Metabolism Efficiency:A SNP-Based Heritability Study of Bangladeshi Adults

Jianjun Gao et al. Environ Health Perspect. 2015 Oct.

Abstract

Background: Consumption of arsenic-contaminated drinking water adversely affects health. There is interindividual variation in arsenic metabolism efficiency, partially due to genetic variation in the arsenic methyltransferase (AS3MT) gene region.

Objectives: The goal of this study was to assess the overall contribution of genetic factors to variation in arsenic metabolism efficiency, as measured by the relative concentration of dimethylarsinic acid (DMA%) in urine.

Methods: Using data on genome-wide single nucleotide polymorphisms (SNPs) and urinary DMA% for 2,053 arsenic-exposed Bangladeshi individuals, we employed various SNP-based approaches for heritability estimation and polygenic modeling.

Results: Using data on all participants, the percent variance explained (PVE) for DMA% by all measured and imputed SNPs was 16% (p = 0.08), which was reduced to 5% (p = 0.34) after adjusting for AS3MT SNPs. Using information on close relatives only, the PVE was 63% (p = 0.0002), but decreased to 41% (p = 0.01) after adjusting for AS3MT SNPs. Regional heritability analysis confirmed 10q24.32 (AS3MT) as a major arsenic metabolism locus (PVE = 7%, p = 4.4 × 10(-10)), but revealed no additional regions. We observed a moderate association between a polygenic score reflecting elevated DMA% (composed of thousands of non-AS3MT SNPs) and reduced skin lesion risk in an independent sample (p < 0.05). We observed no associations for SNPs reported in prior candidate gene studies of arsenic metabolism.

Conclusions: Our results suggest that there are common variants outside of the AS3MT region that influence arsenic metabolism in Bangladeshi individuals, but the effects of these variants are very weak compared with variants near AS3MT. The high heritability estimates observed using family-based heritability approaches suggest substantial effects for rare variants and/or unmeasured environmental factors.

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Conflict of interest statement

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

The authors declare they have no actual or potential competing financial interests.

Figures

Figure 1
Figure 1
Regional heritability estimates (A) and corresponding p-values (B) for DMA%, excluding close relatives (KIBS < 0.05, n = 1,338). Estimates were obtained using measured and imputed SNPs with a window size 100 SNPs with a 50 SNP overlap between windows. A total of 4,924 tests were conducted. The red line represents the Bonferroni-corrected p-value threshold. The two adjacent/overlapping windows that surpass the p-value threshold reside in the 10q24.32 region and are labeled “w1” and “w2.”
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