High exposure variance enables candidate biomarker detection in a small EWAS of methylmercury-exposed Peruvian adults

Background: Epigenome-wide association studies (EWAS) are a highly promising approach that can inform precision environmental health. However, current EWAS are underpowered and increasing sample sizes will require substantial resources. Therefore, alternative approaches for identifying candidate biomarkers through EWAS are critical. Here, we provide proof of principle that maximizing exposure variance in EWAS enables effective candidate biomarker detection, even in small sample sizes. Methods: We profiled genome-wide DNA methylation in whole blood from individuals from Madre de Dios, Peru, with either high methylmercury (MeHg) exposure (> 10 µg/g total hair mercury; N = 16) or low MeHg exposure (< 1 µg/g total hair mercury; N = 16). Results: We identified nine differentially methylated CpG sites (FDR < 0.05), which is comparable to the number identified by much larger EWAS. The most significantly different CpG site was in an intronic enhancer of the SLC5A7 gene, which encodes the L-type amino acid transporter 1 (LAT1) that facilitates MeHg transport. Our Gene Ontology and transcription factor motif enrichment analyses identified genes involved in outcomes linked to MeHg toxicity, including immune response, neurotoxicity, and type 2 diabetes (T2D). Conclusions: Similar EWAS in global populations with known high exposure variance can be leveraged to develop targeted, custom sequencing panels and microarrays limited to replicated, validated biomarkers of a given exposure.