We expand upon prior work (Gibbons et al., 2012) relating childhood stressor effects, particularly harsh childhood environments, to risky behavior and ultimately physical health by adding longer-term outcomes – deoxyribonucleic acid (DNA) methylation-based measures of accelerated aging (DNAm-aging). Further, following work on the effects of early exposure to danger (McLaughlin et al., 2014), we also identify an additional pathway from harsh childhood environments to DNAm-aging that we label the danger/FKBP5 pathway, which includes early exposure to dangerous community conditions that are thought to impact glucocorticoid regulation and pro-inflammatory mechanisms. Because different DNAm-aging indices provide different windows on accelerated aging, we contrast effects on early indices of DNAm-aging based on chronological age with later indices that focused on predicting biological outcomes. We utilize data from Family and Community Health Study participants (N = 449) from age 10 to 29. We find that harshness influences parenting, which, in turn, influences accelerated DNAm-aging through the risky cognitions and substance use (i.e., behavioral) pathway outlined by Gibbons et al. (2012). Harshness is also associated with increased exposure to threat/danger, which, in turn, leads to accelerated DNAm-aging through effects on FKBP5 activity and enhanced pro-inflammatory tendencies (i.e., the danger/FKBP5 pathway).

Identifying the mechanisms linking early experiences, genetic risk factors, and their interaction with later health consequences is central to the development of preventive interventions and identifying potential boundary conditions for their efficacy. In the current investigation of 412 African American adolescents followed across a 20-year period, we examined change in body mass index (BMI) across adolescence as one possible mechanism linking childhood adversity and adult health. We found associations of childhood adversity with objective indicators of young adult health, including a cardiometabolic risk index, a methylomic aging index, and a count of chronic health conditions. Childhood adversities were associated with objective indicators indirectly through their association with gains in BMI across adolescence and early adulthood. We also found evidence of an association of genetic risk with weight gain across adolescence and young adult health, as well as genetic moderation of childhood adversity's effect on gains in BMI, resulting in moderated mediation. These patterns indicated that genetic risk moderated the indirect pathways from childhood adversity to young adult health outcomes and childhood adversity moderated the indirect pathways from genetic risk to young adult health outcomes through effects on weight gain during adolescence and early adulthood.

The present study extends prior research on the link between neighborhood disadvantage and chronic illness by testing an integrated model in which neighborhood characteristics exert effects on health conditions through accelerated cardiometabolic aging. Hypotheses were tested using a sample of 408 African Americans from the Family and Community Health Study. Using four waves of data spanning young adulthood (ages 18–29), we first found durable effects of neighborhood disadvantage on accelerated cardiometabolic aging and chronic illness. Then, we used marginal structural modeling to adjust for potential neighborhood selection effects. As expected, accelerated cardiometabolic aging was the biopsychosocial mechanism that mediated much of the association between neighborhood disadvantage and chronic illness. This finding provides additional support for the view that neighborhood disadvantage can influence morbidity and mortality by creating social contexts that becomes biologically embedded. Perceived neighborhood collective efficacy served to buffer the relationship between neighborhood disadvantage and biological aging, identifying neighborhood-level resilience factor. Overall, our results indicate that neighborhood context serves as a fundamental cause of weathering and accelerated biological aging. Residing in a disadvantaged neighborhood increases biological wear and tear that ultimately leads to onset of chronic illness, but access to perceived collective efficacy buffers the impact of these neighborhood effects. From an intervention standpoint, identifying such an integrated model may help inform future health-promoting interventions.

Parent–child relationships have long-term effects on health, particularly later inflammation and depression. We hypothesized that these effects would be mediated by later romantic partner relationships and elevated stressors in young adulthood, helping promote chronic, low grade, inflammation as well as depressive symptoms, and driving their covariation. It has been proposed recently that youth experiencing harsher parenting may also develop a stronger association between inflammation and depressive symptoms in adulthood and altered effects of stressors on outcomes. In the current investigation, we test these ideas using an 18-year longitudinal study of N = 413 African American youth that provides assessment of the parent–child relationship (at age 10), pro-inflammatory cytokine profile and depressive symptoms (at age 28), and potential mediators in early young adulthood (assessed at ages 21 and 24). As predicted, the effect of harsher parent–child relationships (age 10) on pro-inflammatory state and increased depressive symptoms at age 28 were fully mediated through young adult stress and romantic partner relationships. In addition, beyond these mediated effects, parent–child relationships at age 10 moderated the concurrent association between inflammation and depressive symptoms, as well as the prospective association between romantic partner relationships and inflammation, and resulted in substantially different patterns of indirect effects from young adult mediators to outcomes. The results support theorizing that the association of depression and inflammation in young adulthood is conditional on earlier parenting, and suggest incorporating this perspective into models predicting long-term health outcomes.

We examined two potentially interacting, connected pathways by which parental supportiveness during early adolescence (ages 1–13) may come to be associated with later African American young adult smoking. The first pathway is between parental supportiveness and young adult stress (age 19), with stress, in turn, predicting increased smoking at age 20. The second pathway is between supportive parenting and tumor necrosis factor (TNF) gene methylation (i.e., TNFm), a proinflammatory epitype, with low levels indicating greater inflammatory potential and forecasting increased risk for smoking in response to young adult stress. In a sample of 382 African American youth residing in rural Georgia, followed from early adolescence (age 10–11) to young adulthood (age 20), supportive parenting indirectly predicted smoking via associations with young adult stress, IE = –0.071, 95% confidence interval [–0.132, –0.010]. In addition, supportive parenting was associated with TNFm measured at age 20 (r = .177, p = .001). Further, lower TNFm was associated with a significantly steeper slope (b = 0.583, p = .003) of increased smoking in response to young adult stress compared to those with higher TNFm (b = 0.155, p = .291), indicating an indirect, amplifying role for supportive parenting via TNFm. The results suggest that supportive parenting in early adolescence may play a role in understanding the emergence of smoking in young adulthood.

In the current manuscript, we provide an overview of a research program at the University of Georgia's Center for Family Research designed to expand upon rapid and ongoing developments in the fields of genetics and epigenetics. By placing those developments in the context of translational research on family and community determinants of health and well-being among rural African Americans, we hope to identify novel, modifiable environments and biological processes. In the first section of the article, we review our earlier work on genotypic variation effects on the association between family context and mental and physical health outcomes as well as differential responses to family-based intervention. We then transition to discuss our more recent research on the association of family and community environments with epigenetic processes. In this second section of the article, we begin by briefly reviewing terminology and basic considerations before describing evidence that early environments may influence epigenetic motifs that potentially serve as mediators of long-term effects of early family and community environments on longer term health outcomes. We also provide evidence that genotype may sometimes influence epigenetic outcomes. Finally, we describe our recent efforts to use genome-wide characterization of epigenetic patterns to better understand the biological impact of protective parenting on long-term shifts in inflammatory processes and its potential implications for young adult health. As will be clear, research on epigenetics as a mediator of the connections between family/community processes and a range of health outcomes is still in its infancy, but the potential to develop important insights regarding mechanisms linking modifiable environments to biological processes and long-term health outcomes already is coming into view.

For the past quarter century, scientists at the Center for Family Research at the University of Georgia have conducted research designed to promote understanding of normative developmental trajectories among low socioeconomic status African American children, youths, and young adults. In this paper, we describe a recent expansion of this research program using longitudinal, epidemiological studies and randomized prevention trials to test hypotheses about the origins of disease among rural African American youths. The contributions of economic hardship, downward mobility, neighborhood poverty, and racial discrimination to allostatic load and epigenetic aging are illustrated. The health benefits of supportive family relationships in protecting youths from these challenges are also illustrated. A cautionary set of studies is presented showing that some psychosocially resilient youths demonstrate high allostatic loads and accelerated epigenetic aging, suggesting that, for some, “resilience is just skin deep.” Finally, we end on an optimistic note by demonstrating that family-centered prevention programs can have health benefits by reducing inflammation, helping to preserve telomere length, and inhibiting epigenetic aging.

Building upon various lines of research, we posited that methylation of the oxytocin receptor gene (OXTR) would mediate the effect of adult adversity on increased commitment to negative schemas and in turn the development of depression. We tested our model using structural equation modeling and longitudinal data from a sample of 100 middle-aged, African American women. The results provided strong support for the model. Analysis of the 12 CpG sites available for the promoter region of the OXTR gene identified four factors. One of these factors was related to the study variables, whereas the others were not. This factor mediated the effect of adult adversity on schemas relating to pessimism and distrust, and these schemas, in turn, mediated the impact of OXTR methylation on depression. All indirect effects were statistically significant, and they remained significant after controlling for childhood trauma, age, romantic relationship status, individual differences in cell types, and average level of genome-wide methylation. These finding suggest that epigenetic regulation of the oxytocin system may be a mechanism whereby the negative cognitions central to depression become biologically embedded.

This study investigated the influences of neighborhood factors (residential stability and neighborhood disadvantage) and variants of the serotonin transporter linked polymorphic region (5-HTTLPR) genotype on the development of substance use among African American children aged 10–24 years. To accomplish this, a harmonized data set of five longitudinal studies was created via pooling overlapping age cohorts to establish a database with 2,689 children and 12,474 data points to span ages 10–24 years. A description of steps used in the development of the harmonized data set is provided, including how issues such as the measurement equivalence of constructs were addressed. A sequence of multilevel models was specified to evaluate Gene × Environment effects on growth of substance use across time. Findings indicated that residential instability was associated with higher levels and a steeper gradient of growth in substance use across time. The inclusion of the 5-HTTLPR genotype provided greater precision to the relationships in that higher residential instability, in conjunction with the risk variant of 5-HTTLPR (i.e., the short allele), was associated with the highest level and steepest gradient of growth in substance use across ages 10–24 years. The findings demonstrated how the creation of a harmonized data set increased statistical power to test Gene × Environment interactions for an under studied sample.

This study was designed to investigate a genetic moderation effect of dopamine receptor 4 gene (DRD4) alleles that have seven or more repeats (long alleles) on an intervention to deter drug use among rural African American adolescents in high-risk families. Adolescents (N = 291, M age = 17) were assigned randomly to the Adults in the Making (AIM) program or to a control condition and were followed for 27.5 months. Adolescents provided data on drug use and vulnerability cognitions three times after pretest. Pretest assessments of caregiver depressive symptoms, disruption in the home, and support toward the adolescent were used to construct a family risk index. Adolescents living in high-risk families who carried at least one DRD4 long allele and were assigned to the control condition evinced greater escalations in drug use than did (a) adolescents who lived in high-risk families, carried the DRD4 long allele, and were assigned to AIM, or (b) adolescents assigned to either condition who carried no DRD4 long alleles. AIM-induced reductions in vulnerability cognitions were responsible for the Family Risk × AIM × DRD4 status drug use prevention effects. These findings support differential susceptibility predictions and imply that prevention effects on genetically susceptible individuals may be underestimated.

We hypothesized that presence of the short allele in the promoter region of the serotonin transporter would moderate the effect of early cumulative socioeconomic status (SES) risk on epigenetic change among African American youth. Contrasting hypotheses regarding the shape of the interaction effect were generated using vulnerability and susceptibility frameworks and applied to data from a sample of 388 African American youth. Early cumulative SES risk assessed at 11–13 years based on parent report interacted with presence of the short allele to predict differential methylation assessed at age 19. Across multiple tests, a differential susceptibility perspective rather than a diathesis–stress framework best fit the data for genes associated with depression, consistently demonstrating greater epigenetic response to early cumulative SES risk among short allele carriers. A pattern consistent with greater impact among short allele carriers also was observed using all cytosine nucleotide–phosphate–guanine nucleotide sites across the genome that were differentially affected by early cumulative SES risk. We conclude that the short allele is associated with increased responsiveness to early cumulative SES risk among African American youth, leading to epigenetic divergence for depression-related genes in response to exposure to heightened SES risk among short allele carriers in a “for better” or “for worse” pattern.

This study was designed to examine the prospective relations of life stress and genetic status with increases in drug use. African Americans (N = 399) in rural Georgia (Wave 1 mean age = 17 years) provided three waves of data across 27.5 months and a saliva sample from which the dopamine receptor D4 (DRD4) gene was genotyped. Multilevel growth curve modeling analysis indicated that emerging adults manifested the highest escalations in drug use when they reported high life stress and carried an allele of DRD4 with 7 or more repeats (7 + R allele). In addition, emerging adults who reported high life stress and carried the 7 + R allele evinced the largest increases in two proximal risk factors for drug use: affiliations with drug-using companions and drug use vulnerability cognitions. Furthermore, when the Gene × Environment interaction effects on the increases in affiliations with drug-using companions and vulnerability cognitions were entered into the model forecasting drug use, the Life Stress × DRD4 Status interaction on drug use became nonsignificant in the presence of the risk mechanisms. This finding provides an example of “second generation” Gene × Environment interaction research in which the interaction's effects on proximal risk mechanisms account for its effects on outcomes.

This study examined the prospective relations of adolescents' perceptions of discrimination and their genetic status with increases in conduct problems. Participants were 461 African American youths residing in rural Georgia (Wave 1 mean age = 15.5 years) who provided three waves of data and a saliva sample from which a polymorphism in the SCL6A4 (serotonin transporter [5-HTT]) gene polymorphism known as the 5-HTT linked promoter region (5-HTTLPR) was genotyped. Data analyses using growth curve modeling indicated that perceived discrimination was significantly related to the slope of conduct problems. As hypothesized, interactions between perceived discrimination and genetic status emerged for male but not female youths. Compared with those carrying two copies of the long allele variant of 5-HTTLPR, male youths carrying one or two copies of its short allele variant evinced higher rates of conduct problems over time when they perceived high levels of racial discrimination. These findings are consistent with resilience and differential susceptibility propositions stating that genes can both foster sensitivity to adverse events and confer protection from those events.