Introduction: Per- and polyfluroalkyl substances (PFAS) are persistent environmental pollutants known as “forever chemicals” that bioaccumulate and cause adverse health effects. The US Environmental Protection Agency (EPA) has proposed to designate PFAS as hazardous substances and implement measures to eliminate perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) from food and water sources. Understanding the genetic mechanisms regulating PFAS metabolism and clearance may facilitate the development of novel interventions to reduce their body burden. We aim to identify genetic determinants of plasma PFAS levels. Methods: We performed genome-wide association analyses (GWAS) of plasma PFOA and PFOS among 9992 White participants from the Canadian Longitudinal Study of Aging (CLSA) cohort. After genomic control, genetic variants reaching suggestive significance (P<1E-4) were further evaluated for replication using summary statistics from 6,136 Finland men from the Metabolic Syndrome in Men (METSIM) study. PFOS and PFOA were quantified using the untargeted Metabolon platform in both cohorts. GWAS results from the two cohorts were meta-analyzed using METAL software. Variants achieving nominal significance (P<0.05) in replication analyses and genome-wide significance (P<5E-8) in the meta-analysis and having consistent effect directions were considered significant. Results: As shown in Table , we identified three novel loci associated with plasma PFOS concentrations: a missense (stop gained) variant in ABCG2 (rs2231142), an intronic variant in CYP2C9 (rs112704334), and an intergenic variant (rs148375281). The minor T allele of ABCG2 rs2231142 was associated with higher PFOS levels, whereas the minor alleles of rs112704334 and rs148375281 were associated with lower PFOS levels. No genome-wide significant variants were identified for PFOA. The ABCG2 locus contains genes involved in xenobiotics transportation in the kidney. The CYP2C9 locus contains genes encoding enzymes of the cytochrome P450 family, which are important for xenobiotics metabolism. Conclusion: We identified three novel and functionally relevant loci influencing blood PFOS levels. These findings provide new insight into the genetic regulation of PFAS metabolism and may inform future strategies to reduce PFAS accumulation in humans.
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