Independent Maternal and Fetal Genetic Effects on Midgestational Circulating Levels of Environmental Pollutants

Abstract

Maternal exposure to environmental pollutants could affect fetal brain development and increase autism spectrum disorder (ASD) risk in conjunction with differential genetic susceptibility. Organohalogen congeners measured in maternal midpregnancy blood samples have recently shown significant, but negative associations with offspring ASD outcome. We report the first large-scale maternal and fetal genetic study of the midpregnancy serum levels of a set of 21 organohalogens in a subset of 790 genotyped women and 764 children collected in California by the Early Markers for Autism (EMA) Project. Levels of PCB (polychlorinated biphenyl) and PBDE (polybrominated diphenyl ether) congeners showed high maternal and fetal estimated SNP-based heritability (h2g) accounting for 39–99% of the total variance. Genome-wide association analyses identified significant maternal loci for p,p′-DDE (P = 7.8 × 10−11) in the CYP2B6 gene and for BDE-28 (P = 3.2 × 10−8) near the SH3GL2 gene, both involved in xenobiotic and lipid metabolism. Fetal genetic loci contributed to the levels of BDE-100 (P = 4.6 × 10−8) and PCB187 (P = 2.8 × 10−8), near the potential metabolic genes LOXHD1 and PTPRD, previously implicated in neurodevelopment. Negative associations were observed for BDE-100, BDE153, and the sum of PBDEs with ASD, partly explained by genome-wide additive genetic effects that predicted PBDE levels. Our results support genetic control of midgestational biomarkers for environmental exposures by nonoverlapping maternal and fetal genetic determinants, suggesting that future studies of environmental risk factors should take genetic variation into consideration. The independent influence of fetal genetics supports previous hypotheses that fetal genotypes expressed in placenta can influence maternal physiology and the transplacental transfer of organohalogens.

A profile and review of findings from the Early Markers for Autism study: unique contributions from a population-based case–control study in California

“…DNA was extracted from a subset of 790 maternal cell pellets and 764 neonatal bloodspots and 675,000 SNPs were genotyped across the genome using standard protocols and quality assessment, as previously described [ 41 ]. The genotyped samples included 366 ASD mother–child pairs and 369 control pairs [ 42 , 43 ]. The ID cases and ASD cases identified through reclassification of those originally enrolled as ID were not included in the genome-wide genotyping due to budget limitations, but were used for analyzing specific candidate genetic factors [ 44 ].…”

“…We hypothesized that the most likely genetic candidates for G × E would be the variants associated with the E biomarker itself. Our strategy was thus to perform a quantitative trait locus (QTL) analysis to identify candidate genetic factors that contribute to the inter-individual variation of the E biomarker and then test for interaction with case–control status among those top candidates [ 42 , 43 ]. Given the variety of genetic ancestries in the EMA study population, methods appropriate for mixed-ancestry data were used to avoid ancestry-related false positives, such as adjustment for genome-wide principal components [ 48 ].…”

Prenatal Serum Concentrations of Brominated Flame Retardants and Autism Spectrum Disorder and Intellectual Disability in the Early Markers of Autism Study: A Population-Based Case–Control Study in California

“…Finally, we tested whether adjustment for genetic ancestry of mothers, as measured by principal components (PCs) derived from genome-wide association study (GWAS) data, altered results. Details of GWAS and ancestry analyses in EMA are further described in another publication ( Traglia et al 2017 ); briefly, genome-wide multi-dimensional scaling (MDS) analysis was carried out on high-quality markers genotyped in maternal cell-pellet samples stored from the XAFP and in newborn samples collected through newborn screening, using a pairwise distance genomic matrix and the multi-dimensional scale functions implemented in PLINK software ( Purcell et al 2007 ) (–cluster and –mds plot). The resulting maternal and fetal genetic matrices included 10 PCs that summarized the genetic distance between each maternal and neonatal sample.…”

Certain ortho-hydroxylated brominated ethers are promiscuous kinase inhibitors that impair neuronal signaling and neurodevelopmental processes

“…Recently, several large-scale and systematic reviews have concluded that PBDE exposures impact externalizing behaviors and IQ in children and that BDE-47, -99, and -209 affect learning in animal studies (6)(7)(8)(9). There is also concern for the relationship between environmental toxins like PBDEs and autism spectrum disorders (ASD), though the evidence is less conclusive, especially in human studies (6,(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Given the prevalence of these compounds and their association with behavioral deficits, it is imperative to understand the molecular and cellular mechanisms underlying PBDE neurotoxicity.…”