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Maternal stress during pregnancy can cause alterations to the fetal hypothalamus–pituitary–adrenal (HPA) axis, a phenomenon known as fetal programming that may have lasting effects on offspring outcomes, including depression. Evidence suggests that these effects may vary with respect to the offspring's genetic risk. Nonetheless, few studies have examined these effects into adulthood, when risk for depression onset is highest. The present study builds upon the extant literature by examining the interaction of maternal prenatal perceived stress (MPPS) and offspring HPA-axis polygenic risk to predict offspring depression in early adulthood. A total of 381 mother–child dyads participated in a prospective, longitudinal study that spanned from pregnancy until offspring were 20 years of age. Polygenic risk was defined by a multilocus genetic profile score (MGPS) that reflected the additive risk of three HPA-axis candidate genes. The results indicated that the interaction of MPPS and HPA-axis MGPS confers risk for offspring depression at age 20, in line with the differential susceptibility model. This interaction may be specific to prenatal stress, as maternal stress during early childhood did not interact with genetic risk to predict depression. These findings provide the first evidence that genetic variants that are associated with the HPA axis may act in a polygenic, additive fashion to moderate the association between fetal programming and adult depression.

Sex is an important factor in mental health, and a non-binary view of how variation in sex and gender influence mental health represents a new research frontier that may yield new insights. The recent acceleration of research into sexual orientation, gender identity, and mental health has generally been conducted without sufficient understanding of the opinions of sexual and gender minorities (SGM) toward this research. We surveyed 768 individuals, with an enrichment of LGBTQ+ stakeholders, for their opinions regarding genetic research of SGM and mental health. We found that the key predictors of attitudes toward genetic research specifically on SGM are 1) general attitudes toward genetic and mental health research 2) tolerance of SGM and associated behaviors and 3) age of the participant. Non-heterosexual stakeholder status was significantly associated with increased willingness to participate in genetic research if a biological basis for gender identity were discovered. We also found that heterosexual, cisgender participants with a low tolerance for SGM indicated their SGM views would be positively updated if science showed a biological basis for their behaviors and identities. These findings represent an important first step in understanding and engaging the LGBTQ+ stakeholder community in the context of genetic research.

Although offspring of women exposed to childhood trauma exhibit elevated rates of psychopathology, many children demonstrate resilience to these intergenerational impacts. Among the variety of factors that likely contribute to resilience, epigenetic processes have been suggested to play an important role. The current study used a prospective design to test the novel hypothesis that offspring epigenetic aging – a measure of methylation differences that are associated with infant health outcomes – moderates the relationship between maternal exposure to childhood adversity and offspring symptomatology. Maternal childhood adversity was self-reported during pregnancy via the ACEs survey and the CTQ, which assessed total childhood trauma as well as maltreatment subtypes (i.e., emotional, physical, and sexual abuse). Offspring blood samples were collected at or shortly after birth and assayed on a DNA methylation microarray, and offspring symptomatology was assessed with the CBCL/1.5–5 when offspring were 2–4 years old. Results indicated that maternal childhood trauma, particularly sexual abuse, was predictive of offspring symptoms ( p s = 0.003–0.03). However, the associations between maternal sexual abuse and offspring symptomatology were significantly attenuated in offspring with accelerated epigenetic aging. These findings further our understanding of how epigenetic processes may contribute to and attenuate the intergenerational link between stress and psychopathology.

Background Neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD) display a strong male bias. Androgen exposure is profoundly increased in typical male development, but it also varies within the sexes, and previous work has sought to connect morphological proxies of androgen exposure, including digit ratio and facial morphology, to neurodevelopmental outcomes. The results of these studies have been mixed, and the relationships between androgen exposure and behavior remain unclear. Methods Here, we measured both digit ratio masculinity (DRM) and facial landmark masculinity (FLM) in the same neurodevelopmental cohort ( N = 763) and compared these proxies of androgen exposure to clinical and parent-reported features as well as polygenic risk scores. Results We found that FLM was significantly associated with NDD diagnosis (ASD, ADHD, ID; all p < 0.05 ), while DRM was not. When testing for association with parent-reported problems, we found that both FLM and DRM were positively associated with concerns about social behavior ( ρ = 0.19 , p = 0.004 ; ρ = 0.2 , p = 0.004 , respectively). Furthermore, we found evidence via polygenic risk scores (PRS) that DRM indexes masculinity via testosterone levels ( t = 4.0 , p = 8.8 × 10 - 5 ), while FLM indexes masculinity through a negative relationship with sex hormone binding globulin (SHBG) levels ( t = - 3.3 , p = 0.001 ). Finally, using the SPARK cohort ( N = 9419) we replicated the observed relationship between polygenic estimates of testosterone, SHBG, and social functioning ( t = - 2.3 , p = 0.02 , and t = 4.2 , p = 3.2 × 10 - 5 for testosterone and SHBG, respectively). Remarkably, when considered over the extremes of each variable, these quantitative sex effects on social functioning were comparable to the effect of binary sex itself (binary male: - 0.22 ± 0.05 ; testosterone: - 0.35 ± 0.15 from 0.1%-ile to 99.9%-ile; SHBG: 0.64 ± 0.15 from 0.1%-ile to 99.9%-ile). Limitations In the devGenes and SPARK cohorts, our analyses rely on indirect, rather than direct measurement of androgens and related molecules. Conclusions These findings and their replication in the large SPARK cohort lend support to the hypothesis that increasing net androgen exposure diminishes capacity for social functioning in both males and females.

Black American women are disproportionately exposed to adversities that may have an intergenerational impact on mental health. The present study examined whether maternal exposure to adversity and epigenetic age acceleration (EAA; a biomarker of stress exposure) predicts the socioemotional health of her offspring. During pregnancy, 180 Black American women self-reported experiences of childhood adversity and marginalization-related adversity (i.e., racial discrimination and gendered racial stress) and provided a blood sample for epigenetic assessment. At a three-year follow-up visit, women reported their offspring’s emotional reactivity (an early indicator of psychopathology) via the CBCL/1.5–5. After adjusting for maternal education and offspring sex, results indicated that greater maternal experiences of childhood trauma (β = 0.21, SE(β) = 0.01; p = 0.01) and racial discrimination (β = 0.14, SE(β) = 0.07; p = 0.049) predicted greater offspring emotional reactivity, as did maternal EAA (β = 0.17, SE(β) = 0.09, p = 0.046). Our findings suggest that maternal EAA could serve as an early biomarker for intergenerational risk conferred by maternal adversity, and that ‘maternal adversity’ must be defined more broadly to include social marginalization, particularly for Black Americans.

This dissertation examined the intergenerational associations between maternal childhood adversity and offspring symptoms of psychopathology among Black American mothers and children. Moreover, we explored whether two biological factors related to stress physiology – gut microbiome composition and epigenetic aging – may explain individual differences in offspring susceptibility to maternal childhood adversity. Specifically, we examined how maternal childhood trauma (measured via the Childhood Trauma Questionnaire) and maternal adverse childhood experiences (measured via the ACEs survey) related to offspring internalizing, externalizing, and posttraumatic stress symptomatology. We additionally explored whether maternal childhood maltreatment subtypes (i.e., emotional, physical, and sexual abuse) were differentially related to offspring outcomes. Our findings suggested that both maternal ACEs and maternal childhood trauma, particularly maternal emotional and sexual abuse, are predictive of offspring symptoms of psychopathology, with potentially varying impacts of different types of adversity. We also examined whether variation in the composition of the infant gut microbiome may moderate these intergenerational associations. Although limited evidence supported this hypothesis, we found that the significant association between maternal ACEs and offspring internalizing symptoms was marginally attenuated in offspring with a greater relative abundance of the protective bacteria Lactobacillus. In a separate study, we examined whether offspring epigenetic aging – a measure of DNA methylation differences that are associated with infant health outcomes – may moderate the association between maternal childhood trauma and offspring symptoms. In line with our hypothesis, we found that the significant associations between maternal childhood sexual abuse and offspring internalizing, externalizing, and posttraumatic stress symptoms were attenuated in offspring with accelerated epigenetic aging at birth. Taken together, these results suggest that individual differences in biological factors that relate to the development and regulation of the stress response may influence a child’s susceptibility to stress, including the intergenerational impact of maternal stress. Findings from the current dissertation highlight the utility of better understanding the factors that contribute to these biological differences and whether targeting these modifiable processes could help interrupt the intergenerational transmission of trauma, particularly for those who are most profoundly impacted.

This study aimed to examine associations between maternal childhood abuse and maltreatment, early parenting behaviors, and infant neurodevelopment among African American mother-infant dyads. Maternal adverse childhood experiences (ACEs) were assessed during pregnancy using the Childhood Trauma Questionnaire, and early parenting behaviors were assessed by coding videotaped observations using an adapted version of The Three-Bag Assessment when infants were 3-months of age. Infant neurodevelopment was assessed using the cognitive and motor subscales of the Bayley Scales of Infant and Toddler Development. At the time of this analysis, 59 mother-infant dyads had ACEs exposure, early parenting, and infant neurodevelopment data available from the infant 3-month assessment. Preliminary findings suggest no main effects of maternal adversity on infant neurodevelopment and indicated no significant interaction effects between maternal adversity and early parenting behaviors, although this study may have been underpowered to detect a small effect given the sample size available. It is still possible that these factors predict the rate of neurodevelopment beyond the first three months of life, which will be examined using growth curve analyses in future studies. The overall goal of this ongoing research is to explore parenting behaviors as a key point of intervention that may reduce the intergenerational impact of ACEs on child neurodevelopmental outcomes, thereby breaking the cycle of risk.

Biological sex is an important factor in mental health, and a non-binary view of how variation in sex and gender influence mental health represents a new research frontier that may yield new insights. The recent acceleration of research into sexual orientation, gender identity, and mental health has generally been conducted without sufficient understanding of the opinions of sexual and gender minorities (SGM) toward this research. We surveyed 768 individuals, with an enrichment of LGBTQ stakeholders, for their opinions regarding genetic research of SGM and mental health. We found that the key predictors of attitudes toward genetic research specifically on SGM are 1) general attitudes toward genetic and mental health research 2) tolerance of SGM and associated behaviors 3) non-cisgender stakeholder status and 4) age of the respondent. Non-heterosexual stakeholder status was significantly associated with increased willingness to participate in genetic research if a biological basis for gender identity were discovered. We also found that non-stakeholders with a low tolerance for SGM indicated their SGM views would be positively updated if science showed a biological basis for their behaviors and identities. These findings represent an important first step in understanding and engaging the LGBTQ stakeholder community in the context of genetic research.