Defining despair: Assessing the multidimensionality of despair and its association with suicidality and substance use in early to middle adulthood.

Despite considerable scientific interest in documenting growing despair among U.S. adults, far less attention has been paid to defining despair and identifying appropriate measures. Emerging perspectives from social science and psychiatry outline a comprehensive, multidimensional view of despair, inclusive of individuals' cognitive, emotional, biological and somatic, and behavioral circumstances. The current study assesses the structure and plausibility of this framework based on longitudinal data spanning early to middle adulthood. We identified 40 measures of different dimensions of despair in Wave IV (2008-2009) of the National Longitudinal Study of Adult to Adolescent Health (n = 9149). We used structural equation modeling to evaluate hypothesized relationships among observed and latent variables; we then regressed Wave V (2016-2018) suicidality, heavy drinking, marijuana use, prescription drug misuse, and illicit drug use on latent despair. Our analyses find that models for separate dimensions of despair and overall despair demonstrated excellent fit. Overall despair was a significant predictor of Wave V outcomes, especially suicidality, accounting for 20% of its variation, as compared to 1%-7% of the variation in substance use. Suicidality was consistently associated with all domains of despair; behavioral despair explained the most variation in substance use. Given these results we contend that, lacking direct measures, latent despair can be modeled using available survey items; however, some items are likely better indicators of latent dimensions of despair than others. Moreover, the association between despair and key health behaviors varies considerably, challenging its status as a mechanism simultaneously underlying increased substance use and suicide mortality in the United States. Critically, further validation of measures in other surveys can improve the operationalization of despair and its associated conceptual and theoretical frameworks, thus advancing our understanding of this concept.

Population-based genetic effects for developmental stuttering.

Despite a lifetime prevalence of at least 5%, developmental stuttering, characterized by prolongations, blocks, and repetitions of speech sounds, remains a largely idiopathic speech disorder. Family, twin, and segregation studies overwhelmingly support a strong genetic influence on stuttering risk; however, its complex mode of inheritance combined with thus-far underpowered genetic studies contribute to the challenge of identifying and reproducing genes implicated in developmental stuttering susceptibility. We conducted a trans-ancestry genome-wide association study (GWAS) and meta-analysis of developmental stuttering in two primary datasets: The International Stuttering Project comprising 1,345 clinically ascertained cases from multiple global sites and 6,759 matched population controls from the biobank at Vanderbilt University Medical Center (VUMC), and 785 self-reported stuttering cases and 7,572 controls ascertained from The National Longitudinal Study of Adolescent to Adult Health (Add Health). Meta-analysis of these genome-wide association studies identified a genome-wide significant (GWS) signal for clinically reported developmental stuttering in the general population: a protective variant in the intronic or genic upstream region of SSUH2 (rs113284510, protective allele frequency = 7.49%, Z = -5.576, p = 2.46 × 10-8) that acts as an expression quantitative trait locus (eQTL) in esophagus-muscularis tissue by reducing its gene expression. In addition, we identified 15 loci reaching suggestive significance (p < 5 × 10-6). This foundational population-based genetic study of a common speech disorder reports the findings of a clinically ascertained study of developmental stuttering and highlights the need for further research.

Early Signs of Gut Microbiome Aging: Biomarkers of Inflammation, Metabolism, and Macromolecular Damage in Young Adulthood.

Emerging links between gut microbiota and diseases of aging point to possible shared immune, metabolic, and cellular damage mechanisms, operating long before diseases manifest. We conducted 16S rRNA sequencing of fecal samples collected from a subsample (n = 668) of Add Health Wave V, a nationally representative longitudinal study of adults aged 32-42. An overlapping subsample (n = 345) included whole-blood RNA-seq. We examined associations between fecal taxonomic abundances and dried blood spot-based markers of lipid and glucose homeostasis and C-reactive protein (measured in Wave IV), as well as gene expression markers of inflammation, cellular damage, immune cell composition, and transcriptomic age (measured in Wave V), using Bayesian hierarchical models adjusted for potential confounders. We additionally estimated a co-abundance network between inflammation-related genes and bacterial taxa using penalized Gaussian graphical models. Strong and consistent microbiota associations emerged for HbA1c, glucose, C-reactive protein, and principal components of genes upregulated in inflammation, DNA repair, and reactive oxygen species, with Streptococcus infantis, Pseudomonas spp., and Peptoniphilus as major players for each. This pattern was largely echoed (though attenuated) for immunological cell composition gene sets, and only Serratia varied meaningfully by transcriptomic age. Network co-abundance indicated relationships between Prevotella sp., Bacteroides sp., and Ruminococcus sp. and gut immune/metabolic regulatory activity, and Ruminococcus sp, Dialister, and Butyrivibrio crossotus with balance between Th1 and Th2 inflammation. In conclusion, many common associations between microbiota and major physiologic aging mechanisms are evident in early-mid adulthood and suggest avenues for early detection and prevention of accelerated aging.

Depression, Stressful Life Events, and the Impact of Variation in the Serotonin Transporter: Findings from the National Longitudinal Study of Adolescent to Adult Health (Add Health).

BACKGROUND: The low transcriptionally efficient short-allele of the 5HTTLPR serotonin transporter polymorphism has been implicated to moderate the relationship between the experience of stressful life events (SLEs) and depression. Despite numerous attempts at replicating this observation, results remain inconclusive. METHODS: We examined this relationship in young-adult Non-Hispanic white males and females between the ages of 22 and 26 (n = 4724) participating in the National Longitudinal Study of Adolescent to Adult Health (Add Health) with follow-up information every six years since 1995. RESULTS: Linear and logistic regression models, corrected for multiple testing, indicated that carriers of one or more of the S-alleles were more sensitive to stress than those with two L-alleles and at a higher risk for depression. This relationship behaved in a dose-response manner such that the risk for depression was greatest among those who reported experiencing higher numbers of SLEs. In post-hoc analyses we were not able to replicate an interaction effect for suicide ideation but did find suggestive evidence that the effects of SLEs and 5HTTLPR on suicide ideation differed for males and females. There were no effects of childhood maltreatment. DISCUSSION: Our results provide partial support for the original hypothesis that 5-HTTLPR genotype interacts with the experience of stressful life events in the etiology of depression during young adulthood. However, even with this large sample, and a carefully constructed a priori analysis plan, the results were still not definitive. For the purposes of replication, characterizing the 5HTTLPR in other large data sets with extensive environmental and depression measures is needed.

Social relationships and hypertension in late life: evidence from a nationally representative longitudinal study of older adults.

OBJECTIVE: Social relationships are widely understood to be important for sustaining and improving health and longevity, but it remains unclear how different dimensions of social relationships operate through similar or distinct mechanisms to affect biophysiological markers of aging-related disease over time. METHOD: This study utilized longitudinal data on a nationally representative sample of older adults from the National Social Life, Health, and Aging Project (2005-2011) to examine the prospective associations between social integration and social support and change in systolic blood pressure (SBP) and hypertension risk over time. RESULTS: Although both social relationship dimensions have significant physiological impacts, their relative importance differs by outcome. Low social support was predictive of increase in SBP, whereas low social integration was predictive of increase in risk of hypertension. DISCUSSION: The different roles of relationship characteristics in predicting change in physiological outcomes suggest specific biophysiological stress response and behavioral mechanisms that have important implications for both scientific understandings and effective prevention and control of a leading chronic condition in late life.

Testing the key assumption of heritability estimates based on genome-wide genetic relatedness.

Comparing genetic and phenotypic similarity among unrelated individuals seems a promising way to quantify the genetic component of traits while avoiding the problematic assumptions plaguing twin- and other kin-based estimates of heritability. One approach uses a Genetic Relatedness Estimation through Maximum Likelihood (GREML) model for individuals who are related at less than 0.025 to predict their phenotypic similarity by their genetic similarity. Here we test the key underlying assumption of this approach: that genetic relatedness is orthogonal to environmental similarity. Using data from the Health and Retirement Study (and two other surveys), we show two unrelated individuals may be more likely to have been reared in a similar environment (urban versus nonurban setting) if they are genetically similar. This effect is not eliminated by controls for population structure. However, when we include this environmental confound in GREML models, heritabilities do not change substantially and thus potential bias in estimates of most biological phenotypes is probably minimal.

MAOA genotype, childhood maltreatment, and their interaction in the etiology of adult antisocial behaviors.

BACKGROUND: Maltreatment by an adult or caregiver during childhood is a prevalent and important predictor of antisocial behaviors in adulthood. A functional promoter polymorphism in the monoamine oxidase A (MAOA) gene has been implicated as a moderating factor in the relationship between childhood maltreatment and antisocial behaviors. Although there have been numerous attempts at replicating this observation, results remain inconclusive. METHODS: We examined this gene-environment interaction hypothesis in a sample of 3356 white and 960 black men (aged 24-34) participating in the National Longitudinal Study of Adolescent Health. RESULTS: Primary analysis indicated that childhood maltreatment was a significant risk factor for later behaviors that violate rules and the rights of others (p < .05), there were no main effects of MAOA genotype, and MAOA genotype was not a significant moderator of the relationship between maltreatment and antisocial behaviors in our white sample. Post hoc analyses identified a similar pattern of results among our black sample in which maltreatment was not a significant predictor of antisocial behavior. Post hoc analyses also revealed a main effect of MAOA genotype on having a disposition toward violence in both samples and for violent convictions among our black sample. None of these post hoc findings, however, survived correction for multiple testing (p > .05). Power analyses indicated that these results were not due to insufficient statistical power. CONCLUSIONS: We could not confirm the hypothesis that MAOA genotype moderates the relationship between childhood maltreatment and adult antisocial behaviors.

Genetic bio-ancestry and social construction of racial classification in social surveys in the contemporary United States.

Self-reported race is generally considered the basis for racial classification in social surveys, including the U.S. census. Drawing on recent advances in human molecular genetics and social science perspectives of socially constructed race, our study takes into account both genetic bio-ancestry and social context in understanding racial classification. This article accomplishes two objectives. First, our research establishes geographic genetic bio-ancestry as a component of racial classification. Second, it shows how social forces trump biology in racial classification and/or how social context interacts with bio-ancestry in shaping racial classification. The findings were replicated in two racially and ethnically diverse data sets: the College Roommate Study (N = 2,065) and the National Longitudinal Study of Adolescent Health (N = 2,281).