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. 2017 Apr 3;7(4):1287-1299.
doi: 10.1534/g3.117.039784.

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

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Free PMC article

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

Michela Traglia et al. G3 (Bethesda). .
Free PMC article

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.

Keywords: GWAS; autism spectrum disorders; environmental pollutants; heritability; metabolism; organohalogens.

Figures

Figure 1
Figure 1
Linkage disequilibrium regional genomic plot of maternal genome-wide associated SNPs with congener serum levels. (A) rs7259965 on chromosome 19q13.2 associated with p,p′-DDE levels (β = 0.32, SE = 0.05, P = 7.8 × 10−11) maps to the CYP2B6 gene; (B) rs11789653 on chromosome 9p22.2 associated with BDE-28 (β = 0.65, SE = 0.12, P = 3.2 × 10−8) maps between ADAMTSL1 and SH3GL2 genes. The X-axis represents the genomic position; the Y-axis shows the negative logarithm of the observed association P-value for each tested SNP. Plotted with Locuzoom tool (Pruim et al. 2011).
Figure 2
Figure 2
Linkage disequilibrium regional genomic plot of fetal genome-wide associated SNPs with congener serum levels. (A) rs72692916 on chromosome 9p24.1 associated with PCB187 (β = −0.42, SE = 0.08, P = 2.8 × 10−8); maps to the PTPRD gene; (B) rs72913475 on chromosome 18q21.1 associated with BDE-100 (β = 0.55, SE = 0.1, P = 4.6 × 10−8) maps to the LOXHD1 gene. The X-axis represents the genomic position; the Y-axis shows the negative logarithm of the observed association P-value for each tested SNP. Plotted with Locuzoom tool (Pruim et al. 2011).

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