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

Introduction Phthalates, 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. Objective In 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). Methods The 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. Results We identified four genome-wide significant (p-value <5E-08) loci at chromosome (chr) 3 ( FECHP1 for oxo-MiNP_oh-MiNP ratio), chr6 ( SLC17A1 for MECPP_MEHPP ratio), chr9 ( RAPGEF1 for MBzP), and chr10 ( CYP2C9 for MECPP_MEHPP ratio). Moreover, 113 additional loci were found at suggestive significance (p-value <1E-05). Two CNVs located at chr11 ( MRGPRX1 for oh-MiNP and SLC35F2 for MEP) were also identified. Functional annotation pointed to genes involved in phase I and phase II detoxification, molecular transfer across membranes, and renal excretion. Conclusion Through 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 abstract Highlights The 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.