title: 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 theCYP2B6gene and for BDE-28 (P= 3.2 × 10-8) near theSH3GL2gene, 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 genesLOXHD1andPTPRD, 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.
authors.affiliation: Department of Psychiatry, Weill Institute for Neurosciences and Institute for Human Genetics, University of California, San Francisco, California 94143.
authors.forename: Michela
authors.identifier: 0000-0002-5700-135X
authors.initials: M
authors.lastname: Traglia
authors.affiliation: Autism Research Program, Division of Research, Kaiser Permanente, Oakland, California 94612.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Croen
authors.affiliation: Division of Environmental and Occupational Disease Control, California Department of Public Health, Richmond, California 94804.
authors.forename: Kristen
authors.initials: K
authors.lastname: Lyall
authors.affiliation: Division of Environmental and Occupational Disease Control, California Department of Public Health, Richmond, California 94804.
authors.forename: Gayle C
authors.initials: GC
authors.lastname: Windham
authors.affiliation: Genetic Disease Screening Program, California Department of Public Health, Richmond, California 94804.
authors.forename: Marty
authors.initials: M
authors.lastname: Kharrazi
authors.affiliation: Autism Research Program, Division of Research, Kaiser Permanente, Oakland, California 94612.
authors.forename: Gerald N
authors.initials: GN
authors.lastname: DeLorenze
authors.affiliation: Center for Persons with Disabilities, Utah State University, Logan, Utah 84322.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Torres
authors.affiliation: Department of Psychiatry, Weill Institute for Neurosciences and Institute for Human Genetics, University of California, San Francisco, California 94143 Lauren.Weiss@ucsf.edu.
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Weiss
mesh_terms: D000067877:Autism Spectrum Disorder / Q000097:blood; D004785:Environmental Pollutants / Q000097:blood*; D005260:Female; D005333:Fetus / Q000378:metabolism*; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D007231:Infant, Newborn; D040582:Inheritance Patterns / Q000235:genetics; D016014:Linear Models; D015810:Linkage Disequilibrium / Q000235:genetics; D018811:Maternal Exposure; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011247:Pregnancy
chemical_list: D004785:Environmental Pollutants
keywords: GWAS; autism spectrum disorders; environmental pollutants; heritability; metabolism; organohalogens