title: Hypothesis: genetic and epigenetic risk factors interact to modulate vulnerability and resilience to FASD.
abstract: Fetal alcohol spectrum disorder (FASD) presents a collection of symptoms representing physiological and behavioral phenotypes caused by maternal alcohol consumption. Symptom severity is modified by genetic differences in fetal susceptibility and resistance as well as maternal genetic factors such as maternal alcohol sensitivity. Animal models demonstrate that both maternal and paternal genetics contribute to the variation in the fetus' vulnerability to alcohol exposure. Maternal and paternal genetics define the variations in these phenotypes even without the effect of alcohol in utero, as most of these traits are polygenic, non-Mendelian, in their inheritance. In addition, the epigenetic alterations that instigate the alcohol induced neurodevelopmental deficits can interact with the polygenic inheritance of respective traits. Here, based on specific examples, we present the hypothesis that the principles of non-Mendelian inheritance, or "exceptions" to Mendelian genetics, can be the driving force behind the severity of the prenatal alcohol-exposed individual's symptomology. One such exception is when maternal alleles lead to an altered intrauterine hormonal environment and, therefore, produce variations in the long-term consequences on the development of the alcohol-exposed fetus. Another exception is when epigenetic regulation of allele-specific gene expression generates disequilibrium between the maternal vs. paternal genetic contributions, and thereby, modifies the effect of prenatal alcohol exposure on the fetus. We propose that these situations in which one parent has an exaggerated influence over the offspring's vulnerability to prenatal alcohol are major contributing mechanisms responsible for the variations in the symptomology of FASD in the exposed generation and beyond.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Northwestern University Chicago, IL, USA.
authors.forename: Elif
authors.initials: E
authors.lastname: Tunc-Ozcan
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Northwestern University Chicago, IL, USA.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Sittig
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Northwestern University Chicago, IL, USA.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Harper
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Northwestern University Chicago, IL, USA.
authors.forename: Evan N
authors.initials: EN
authors.lastname: Graf
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Northwestern University Chicago, IL, USA.
authors.forename: Eva E
authors.initials: EE
authors.lastname: Redei
keywords: allele specific expression; prenatal ethanol; rat; second generation; strain differences; thyroid hormones