Genome-wide association study of toxic metals and trace elements reveals novel associations

Abstract

The accumulation of toxic metals in the human body is influenced by exposure and mechanisms involved in metabolism, some of which may be under genetic control. This is the first genome-wide association study to investigate variants associated with whole blood levels of a range of toxic metals. Eleven toxic metals and trace elements (aluminium, cadmium, cobalt, copper, chromium, mercury, manganese, molybdenum, nickel, lead and zinc) were assayed in a cohort of 949 individuals using mass spectrometry. DNA samples were genotyped on the Infinium Omni Express bead microarray and imputed up to reference panels from the 1000 Genomes Project. Analyses revealed two regions associated with manganese level at genome-wide significance, mapping to 4q24 and 1q41. The lead single nucleotide polymorphism (SNP) in the 4q24 locus was rs13107325 (P-value = 5.1 × 10−11, β = −0.77), located in an exon of SLC39A8, which encodes a protein involved in manganese and zinc transport. The lead SNP in the 1q41 locus is rs1776029 (P-value = 2.2 × 10−14, β = −0.46). The SNP lies within the intronic region of SLC30A10, another transporter protein. Among other metals, the loci 6q14.1 and 3q26.32 were associated with cadmium and mercury levels (P = 1.4 × 10−10, β = −1.2 and P = 1.8 × 10−9, β = −1.8, respectively). Whole blood measurements of toxic metals are associated with genetic variants in metal transporter genes and others. This is relevant in inferring metabolic pathways of metals and identifying subsets of individuals who may be more susceptible to metal toxicity.

Polymorphisms in manganese transporters show developmental stage and sex specific associations with manganese concentrations in primary teeth

“…Postnatal dentine showed associations of Mn concentrations with rs1776029 genotypes that are consistent with patterns previously observed in blood of adults where rs1776029 rare allele (A) was associated with higher Mn and rs12064812 rare allele C with lower Mn (Ng et al, 2015; Wahlberg et al, 2016), while for prenatal dentine, the associations were in opposite directions. We hypothesize that this pattern could reflect the new conditions experienced by the child after birth in respect to nutritional uptake and homeostasis.…”

“…In this study we have evaluated three SNPs in Mn transporter Mn transporter genes SLC30A10.... SLC30A10 and SLC39A8 that have previously been shown to have a significant influence on blood Mn concentrations in adults and have also been associated with neurological symptoms (Ng et al, 2015; Pickrell et al, 2016; Wahlberg et al, 2016). This is however the first study evaluating the influence of these SNPs on Mn regulation in early-life human development and we have observed interesting consistent patterns of associations between these SNPs with Mn concentrations in dentine representative of different early life stages.…”

“…Recent studies have shown that common single nucleotide polymorphisms (SNPs) in Mn transporter genes SLC30A10 (efflux transporter) and SLC39A8 (influx transporter) modify Mn concentrations in adults and are also associated with neurological symptoms (Ng et al, 2015; Pickrell et al, 2016; Wahlberg et al, 2016). These finding suggests that SNPs in Mn transporters may influence the brain, possibly via interference with Mn homeostasis.…”

Urinary levels of trace elements among primary school-aged children from Italy: The contribution of smoking habits of family members

“…Regarding the possible influence of BMI on ETS intake determined by differences in respiratory rates and respiratory capacities in pediatric age, it should be considered a research agenda of the studies performed in this field. Likewise, since a recent genome-wide association study (Ng et al, 2015) demonstrated a significant relationship between blood levels of several toxic metals and genetic variants in metal transporter genes, future researches should carefully consider also the genetic influence on accumulation of trace elements in the human body and their urinary excretion.…”

Direct Comparison of Manganese Detoxification/Efflux Proteins and Molecular Characterization of ZnT10 Protein as a Manganese Transporter

“…Recent significant findings show that loss-of-function mutations of the ZnT10/SLC30A10 gene result in parkinsonism with hypermanganesemia, a syndrome of hepatic cirrhosis, polycythemia, and dystonia (22,23). ZnT10 is localized to the plasma membrane and is functional in manganese metabolism by effluxing cytosolic manganese (24,25). ZnT10 is also involved in zinc homeostasis in subcellular localization (26,27).…”