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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 pooled urine 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_MEHHP ratio), chr9 (RAPGEF1 for MBzP), and chr10 (CYP2C9 for MECPP_MEHHP ratio). Moreover, 115 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, transmembrane transfer, and renal excretion.
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Chromosome analysis (CA) and chromosomal microarray analysis (CMA) have been successfully used to diagnose genetic disorders. However, many conditions remain undiagnosed due to limitations in resolution (CA) and detection of only unbalanced events (CMA). Optical genome mapping (OGM) has the potential to address these limitations by capturing both structural variants (SVs) resulting in copy number changes and balanced rearrangements with high resolution. In this study, we investigated OGM's concordance using 87 SVs previously identified by CA, CMA, or Southern blot. Overall, OGM was 98% concordant with only three discordant cases: (1) uncalled translocation with one breakpoint in a centromere; (2) uncalled duplication with breakpoints in the pseudoautosomal region 1; and (3) uncalled mosaic triplication originating from a marker chromosome. OGM provided diagnosis for three previously unsolved cases: (1) disruption of the SON gene due to a balanced reciprocal translocation; (2) disruption of the NBEA gene due to an inverted insertion; (3) disruption of the TSC2 gene due to a mosaic deletion. We show that OGM is a valid method for the detection of many types of SVs in a single assay and is highly concordant with legacy cytogenomic methods; however, it has limited SV detection capabilities in centromeric and pseudoautosomal regions.