From single metals to mixtures: uncovering genetic risk factors for metal exposure in disease-free individuals from the EPIC-Spain cohort

Background Accumulation of metals in the human body results from the interplay between environmental exposure—primarily through diet—and genetic susceptibility. Genome-wide association studies (GWAS) enable hypothesis-free identification of single-nucleotide polymorphisms (SNPs) associated with metal levels, but evidence from European populations is scarce. Our aim was to identify SNPs associated with metal levels including a mixture approach. Methods We conducted a cross-sectional GWAS in 950 disease-free adults from the EPIC-Spain cohort. Plasma concentrations of 14 metals were measured by inductively coupled plasma mass spectrometry. Metals were analyzed as the outcome, individually and as mixtures. Multivariable linear regression models were adjusted for sex, age, center, and ancestry principal components. Functional annotation of the SNPs identified was performed to explore their biological relevance. Results A total of 33 SNPs were significantly associated with copper (Cu), 14 with molybdenum (Mo), 2 with chromium (Cr), 1 with tungsten (W), and 7 with the non-essential mixture. Variants rs121907998 and rs139633388 mapped to genes with established roles in Cu transport and homeostasis ( ATP7B and CP , respectively). For Mo, enrichment analyses highlighted neurodevelopmental processes driven by PTPRZ1 . A locus in MYO3A was associated with the non-essential mixture. Conclusions To our knowledge, this is the first GWAS to integrate a metal mixture approach. The identified variants, particularly for Cu and Mo, revealed metabolic pathways involved in plasma levels of metals, both individually and as mixtures. Moreover, they may serve to identify individuals at higher risk of metal toxicity. Replication in larger cohorts using additional biological matrices is warranted.