Objective: To test whether polymorphisms of the glutathione S-transferase P1 gene (GSTP1) act in the mother during pregnancy to contribute to the phenotype of autistic disorder (AD) in her fetus.
Design: Transmission disequilibrium testing (TDT) in case mothers and maternal grandparents.
Setting: Autistic disorder may result from multiple genes and environmental factors acting during pregnancy and afterward. Teratogenic alleles act in mothers during pregnancy to contribute to neurodevelopmental disorders in their offspring; however, only a handful have been identified. GSTP1 is a candidate susceptibility gene for AD because of its tissue distribution and its role in oxidative stress, xenobiotic metabolism, and JNK regulation.
Participants: We genotyped GSTP1*G313A and GSTP1*C341T polymorphisms in 137 members of 49 families with AD. All probands received a clinical diagnosis of AD by Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule-Generic testing.
Main outcome measures: Association of haplotypes with AD was tested by the TDT-Phase program, using the expectation-maximization (EM) algorithm for uncertain haplotypes and for incomplete parental genotypes, with standard measures of statistical significance.
Results: The GSTP1*A haplotype was overtransmitted to case mothers (P = .01 [P = .03 using permutation testing]; odds ratio, 2.67 [95% confidence interval, 1.39-5.13]). Results of the combined haplotype and genotype analyses suggest that the GSTP1-313 genotype alone determined the observed haplotype effect.
Conclusions: Overtransmission of the GSTP1*A haplotype to case mothers suggests that action in the mother during pregnancy likely increases the likelihood of AD in her fetus. If this is confirmed and is a result of a gene-environment interaction occurring during pregnancy, these findings could lead to the design of strategies for prevention or treatment.