Parental Occupational Exposure to Solvents and Autism Spectrum Disorder: An Exploratory Look at Gene-Environment Interactions

Background: There is some evidence that parental occupational exposure to solvents may be associated with autism spectrum disorder (ASD). Similarly, there are a number of genetic factors that are associated with ASD. However, little research has evaluated potential gene-solvent interactions in the etiology of ASD.

Objectives: To investigate the joint effect of genetic variants and parental occupational solvent exposure in ASD.

Methods: Demographic, health, genetic microarray analysis, and parental occupational history information were collected for 416 children with ASD, 298 typically developing (TD) children and their parents as part of the CHildhood Autism Risks from Genetics and Environment study. Solvent exposure was assessed by two industrial hygienists. For each job, the frequency and intensity of potential solvent exposure was estimated and a binary and semi-quantitative cumulative exposure variable was determined. To assess gene-solvent interaction, the total number of minor alleles at each locus was fit in a model that contained the single nucleotide polymorphism (SNP) alone, solvent alone, and a SNP x solvent interaction term. The ratio of odds ratios (ROR) and 95% confidence interval were used to assess the effect of gene-solvent interaction on a multiplicative scale on the risk of ASD. The relative excess risk for interaction (RERI) was used to estimate interactions on an additive scale. In this model, the dominant model was used to create binary genotype variables that were put into the logistic model described above.

Results: Statistically significant (p ≤ 0.05) interactions were found for both the additive and multiplicative models. Multiplicative interactions were found between solvents and a number of serotonin, major histocompatibility complex, inflammatory, and metabolism gene variants in the risk of ASD (n = 35 variants; ROR > 2; p ≤ .01). Similarly, there were a number of superadditive interactions between solvents and serotonin, major histocompatibility, inflammatory, and metabolism gene variants (n = 23 variants; RERI > 0). Monotonic superadditive interactions were found between solvents and two HTR1A serotonin gene variants and two RORA gene variant (RERI > 1; p ≤ 0.05). There were also a number of subadditive interactions between solvents and antioxidant metabolism genes, major histocompatibility complex, inflammatory, and metabolism gene variants (GLRX3, HLA-C*HLA-B, HTR2A, HTR7, TGFB2, TNXB, VEGFA; RERI < 0, p ≤ 0.05).

Conclusions: This study indicates that the joint effects of certain antioxidant metabolism, major histocompatibility complex, inflammatory, and serotonin gene variants and parental occupational exposure to solvents may be associated with ASD. This is one of the first studies to evaluate potential gene-environment interactions in the risk of ASD. Additional studies with a larger sample size to confirm and extend these findings are needed.