Common genetic variants associated with urinary phthalate levels in children: a genome-wide study

Abstract

AbstractIntroductionPhthalates, or dieters of phthalic acid, are a ubiquitous type of plasticizer used in a variety of common consumer and industrial products. They act as endocrine disruptors and are associated with increased risk for several diseases. Once in the body, phthalates are metabolized through partially known mechanisms, involving phase I and phase II enzymes.ObjectiveIn this study we aimed to identify common single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) associated with the metabolism of phthalate compounds in children through genome-wide association studies (GWAS).MethodsThe study used data from 1,044 children with European ancestry from the Human Early Life Exposome (HELIX) cohort. Ten phthalate metabolites were assessed in a two-void urine pool collected at the mean age of 8 years. Six ratios between secondary and primary phthalate metabolites were calculated. Genome-wide genotyping was done with the Infinium Global Screening Array (GSA) and imputation with the Haplotype Reference Consortium (HRC) panel. PennCNV was used to estimate copy number variants (CNVs) and CNVRanger to identify consensus regions. GWAS of SNPs and CNVs were conducted using PLINK and SNPassoc, respectively. Subsequently, functional annotation of suggestive SNPs (p-value <1E-05) was done with the FUMA web-tool.ResultsWe identified four genome-wide significant (p-value <5E-08) loci at chromosome (chr) 3 (FECHP1for oxo-MiNP_oh-MiNP ratio), chr6 (SLC17A1for MECPP_MEHPP ratio), chr9 (RAPGEF1for MBzP), and chr10 (CYP2C9for MECPP_MEHPP ratio). Moreover, 113 additional loci were found at suggestive significance (p-value <1E-05). Two CNVs located at chr11 (MRGPRX1for oh-MiNP andSLC35F2for MEP) were also identified. Functional annotation pointed to genes involved in phase I and phase II detoxification, molecular transfer across membranes, and renal excretion.ConclusionThrough genome-wide screenings we identified known and novel loci implicated in phthalate metabolism in children. Genes annotated to these loci participate in detoxification and renal excretion.Graphical abstractHighlightsThe genetic variation involved in phthalate detoxification in humans is partially known.We identified four loci at genome-wide significance, and 113 at suggestive significance, some of them being novel.Two copy number variants were also identified.Functional annotation highlighted genes in phase I and II detoxification and renal excretion.