Socioeconomic inequalities in molecular risk for chronic diseases observed in young adulthood.

Many common chronic diseases of aging are negatively associated with socioeconomic status (SES). This study examines whether inequalities can already be observed in the molecular underpinnings of such diseases in the 30s, before many of them become prevalent. Data come from the National Longitudinal Study of Adolescent to Adult Health (Add Health), a large, nationally representative sample of US subjects who were followed for over two decades beginning in adolescence. We now have transcriptomic data (mRNA-seq) from a random subset of 4,543 of these young adults. SES in the household-of-origin and in young adulthood were examined as covariates of a priori-defined mRNA-based disease signatures and of specific gene transcripts identified de novo. An SES composite from young adulthood predicted many disease signatures, as did income and subjective status. Analyses highlighted SES-based inequalities in immune, inflammatory, ribosomal, and metabolic pathways, several of which play central roles in senescence. Many genes are also involved in transcription, translation, and diverse signaling mechanisms. Average causal-mediated effect models suggest that body mass index plays a key role in accounting for these relationships. Overall, the results reveal inequalities in molecular risk factors for chronic diseases often decades before diagnoses and suggest future directions for social signal transduction models that trace how social circumstances regulate the human genome.

Institutional Context Shapes the Physical Health of College Graduates Differently for U.S. White, Black, and Hispanic Adults.

Greater educational attainment is generally associated with healthier and longer lives. However, important heterogeneity in who benefits from educational attainment, how much, and why remains underexplored. In particular, in the United States, the physical health returns to educational attainment are not as large for minoritized racial and ethnic groups compared with individuals racialized as White. Yet, our current understanding of ethnoracial differences in educational health disparities is limited by an almost exclusive focus on the quantity of education attained without sufficient attention to heterogeneity within educational attainment categories, such as different institution types among college graduates. Using biomarker data from the National Longitudinal Study of Adolescent to Adult Health (Add Health), we test whether the physical health of college graduates in early adulthood (aged 24-32) varies by institution type and for White, Black, and Hispanic adults. In considering the role of the college context, we conceptualize postsecondary institutions as horizontally stratified and racialized institutional spaces with different implications for the health of their graduates. Finally, we quantify the role of differential attendance at and returns to postsecondary institution type in shaping ethnoracialized health disparities among college graduates in early adulthood.

Life-course trajectories of body mass index from adolescence to old age: Racial and educational disparities.

No research exists on how body mass index (BMI) changes with age over the full life span and social disparities therein. This study aims to fill the gap using an innovative life-course research design and analytic methods to model BMI trajectories from early adolescence to old age across 20th-century birth cohorts and test sociodemographic variation in such trajectories. We conducted the pooled integrative data analysis (IDA) to combine data from four national population-based NIH longitudinal cohort studies that collectively cover multiple stages of the life course (Add Health, MIDUS, ACL, and HRS) and estimate mixed-effects models of age trajectories of BMI for men and women. We examined associations of BMI trajectories with birth cohort, race/ethnicity, parental education, and adult educational attainment. We found higher mean levels of and larger increases in BMI with age across more recent birth cohorts as compared with earlier-born cohorts. Black and Hispanic excesses in BMI compared with Whites were present early in life and persisted at all ages, and, in the case of Black-White disparities, were of larger magnitude for more recent cohorts. Higher parental and adulthood educational attainment were associated with lower levels of BMI at all ages. Women with college-educated parents also experienced less cohort increase in mean BMI. Both race and education disparities in BMI trajectories were larger for women compared with men.

Socioeconomic Inequalities and Molecular Risk for Aging in Young Adulthood.

Diverse manifestations of biological aging often reflect disparities in socioeconomic status (SES). In this paper, we examine associations between indicators of SES and an mRNA-based aging signature during young adulthood, before clinical indications of aging are common. We use data from wave V (2016-2018) of the National Longitudinal Study of Adolescent to Adult Health, a nationally representative study of adults aged 33-43 years, with transcriptomic data from a subset of 2,491 participants. Biological aging is measured using 1) a composite transcriptomic aging signature previously identified by Peters et al.'s out-of-sample meta-analysis (Nat Commun. 2015;6:8570) and 2) 9 subsets that represent functional pathways of coexpressed genes. SES refers to income, education, occupation, subjective social status, and a composite measure combining these 4 dimensions. We examine hypothesized mechanisms through which SES could affect aging: body mass index, smoking, health insurance status, difficulty paying bills, and psychosocial stress. We find that SES-especially the composite measure and income-is associated with transcriptomic aging and immune, mitochondrial, ribosomal, lysosomal, and proteomal pathways. Counterfactual mediational models suggest that the mediators partially account for these associations. The results thus reveal that numerous biological pathways associated with aging are already linked to SES in young adulthood.

Uncovering the genetic architecture of broad antisocial behavior through a genome-wide association study meta-analysis.

Despite the substantial heritability of antisocial behavior (ASB), specific genetic variants robustly associated with the trait have not been identified. The present study by the Broad Antisocial Behavior Consortium (BroadABC) meta-analyzed data from 28 discovery samples (N = 85,359) and five independent replication samples (N = 8058) with genotypic data and broad measures of ASB. We identified the first significant genetic associations with broad ASB, involving common intronic variants in the forkhead box protein P2 (FOXP2) gene (lead SNP rs12536335, p = 6.32 × 10-10). Furthermore, we observed intronic variation in Foxp2 and one of its targets (Cntnap2) distinguishing a mouse model of pathological aggression (BALB/cJ strain) from controls (BALB/cByJ strain). Polygenic risk score (PRS) analyses in independent samples revealed that the genetic risk for ASB was associated with several antisocial outcomes across the lifespan, including diagnosis of conduct disorder, official criminal convictions, and trajectories of antisocial development. We found substantial genetic correlations of ASB with mental health (depression rg = 0.63, insomnia rg = 0.47), physical health (overweight rg = 0.19, waist-to-hip ratio rg = 0.32), smoking (rg = 0.54), cognitive ability (intelligence rg = -0.40), educational attainment (years of schooling rg = -0.46) and reproductive traits (age at first birth rg = -0.58, father's age at death rg = -0.54). Our findings provide a starting point toward identifying critical biosocial risk mechanisms for the development of ASB.

Cumulative life-course victimization and inflammation in a U.S. national sample: Comparing intersections based on sexual orientation, gender, race/ethnicity, and education.

Violence victimization has been associated with low-grade inflammation. Lesbian, Gay, and Bisexual (LGB) individuals are at greater risk for victimization in childhood and young adulthood compared to heterosexuals. Moreover, the intersection of LGB identity with gender, race/ethnicity, and educational attainment may be differentially associated with victimization rates. However, no previous study has examined the role of cumulative life-course victimization during childhood and young adulthood in the association between 1) LGB identity and low-grade inflammation during the transition to midlife, and 2) intersection of LGB identity with gender, race/ethnicity, and educational attainment and low-grade inflammation during the transition to midlife. We utilized multi-wave data from a national sample of adults entering midlife in the United States- the National Longitudinal Study of Adolescent to Adult Health (Add Health; n = 4573) - and tested four bootstrapped mediation models. Results indicate LGB identity, LGB and White, and LGB and Black identities were indirectly associated with low-grade inflammation during the transition to midlife via higher levels of cumulative life-course victimization. Moreover, among LGB adults, the association between 1) less than college education and 2) some college education, and low-grade inflammation was mediated by cumulative life-course victimization. For LGB females, there was a direct association between identity and low-grade inflammation and this association was mediated by cumulative life-course victimization . Reducing accumulation of victimization could be critical for preventing biological dysregulation and disease onset among LGB individuals, particularly for those with multiple marginalized identities.

Patterns and Life Course Determinants of Black-White Disparities in Biological Age Acceleration: A Decomposition Analysis.

Despite the prominence of the weathering hypothesis as a mechanism underlying racialized inequities in morbidity and mortality, the life course social and economic determinants of Black-White disparities in biological aging remain inadequately understood. This study uses data from the Health and Retirement Study (n = 6,782), multivariable regression, and Kitagawa-Blinder-Oaxaca decomposition to assess Black-White disparities across three measures of biological aging: PhenoAge, Klemera-Doubal biological age, and homeostatic dysregulation. It also examines the contributions of racial differences in life course socioeconomic and stress exposures and vulnerability to those exposures to Black-White disparities in biological aging. Across the outcomes, Black individuals exhibited accelerated biological aging relative to White individuals. Decomposition analyses showed that racial differences in life course socioeconomic exposures accounted for roughly 27% to 55% of the racial disparities across the biological aging measures, and racial disparities in psychosocial stress exposure explained 7% to 11%. We found less evidence that heterogeneity in the associations between social exposures and biological aging by race contributed substantially to Black-White disparities in biological aging. Our findings offer new evidence of the role of life course social exposures in generating disparities in biological aging, with implications for understanding age patterns of morbidity and mortality risks.

Population-based RNA profiling in Add Health finds social disparities in inflammatory and antiviral gene regulation to emerge by young adulthood.

Health in later life varies significantly by individual demographic characteristics such as age, sex, and race/ethnicity, as well as by social factors including socioeconomic status and geographic region. This study examined whether sociodemographic variations in the immune and inflammatory molecular underpinnings of chronic disease might emerge decades earlier in young adulthood. Using data from 1,069 young adults from the National Longitudinal Study of Adolescent to Adult Health (Add Health)-the largest nationally representative and ethnically diverse sample with peripheral blood transcriptome profiles-we analyzed variation in the expression of genes involved in inflammation and type I interferon (IFN) response as a function of individual demographic factors, sociodemographic conditions, and biobehavioral factors (smoking, drinking, and body mass index). Differential gene expression was most pronounced by sex, race/ethnicity, and body mass index (BMI), but transcriptome correlates were identified for every demographic dimension analyzed. Inflammation-related gene expression showed the most pronounced variation as a function of biobehavioral factors (BMI and smoking) whereas type I IFN-related transcripts varied most strongly as a function of individual demographic characteristics (sex and race/ethnicity). Bioinformatic analyses of transcription factor and immune-cell activation based on transcriptome-wide empirical differences identified additional effects of family poverty and geographic region. These results identify pervasive sociodemographic differences in immune-cell gene regulation that emerge by young adulthood and may help explain social disparities in the development of chronic illness and premature mortality at older ages.

Effects of the peer metagenomic environment on smoking behavior.

Recent scholarship suggests that the genomes of those around us affect our own phenotypes. Much of the empirical evidence for such "metagenomic" effects comes from animal studies, where the socio-genetic environment can be easily manipulated. Among humans, it is more difficult to identify such effects given the nonrandom distribution of genes and environments. Here we leverage the as-if-random distribution of grade-mates' genomes conditional on school-level variation in a nationally representative sample. Specifically, we evaluate whether one's peers' genetic propensity to smoke affects one's own smoking behavior net of one's own genotype. Results show that peer genetic propensity to smoke has a substantial effect on an individual's smoking outcome. This is true not only when the peer group includes direct friends, and therefore where the individual plays an active role in shaping the metagenomic context but also when the peer group includes all grade-mates and thus in cases where the individual does not select the metagenomic environment. We explore these effects further and show that a small minority with high genetic risk to smoke ('bad apples') can greatly affect the smoking behavior of an entire grade. The methodology used in this paper offers a potential solution to many of the challenges inherent in estimating peer effects in nonexperimental settings and can be utilized to study a wide range of outcomes with a genetic basis. On a policy level, our results suggest that efforts to reduce adolescent smoking should take into account metagenomic effects, especially bad apples, within social networks.

The Early Life Course of Body Weight and Gene Expression Signatures for Disease.

We examined the way body-weight patterns through the first 4 decades of life relate to gene expression signatures of common forms of morbidity, including cardiovascular disease (CVD), type 2 diabetes (T2D), and inflammation. As part of wave V of the nationally representative National Longitudinal Study of Adolescent to Adult Health (1997-2018) in the United States, mRNA abundance data were collected from peripheral blood (n = 1,132). We used a Bayesian modeling strategy to examine the relative associations between body size at 5 life stages-birth, adolescence, early adulthood, young adulthood, and adulthood-and gene expression-based disease signatures. We compared life-course models that consider critical or sensitive periods, as well as accumulation over the entire period. Our results are consistent with a sensitive-period model when examining CVD and T2D gene expression signatures: Birth weight has a prominent role for the CVD and T2D signatures (explaining 33.1% and 22.1%, respectively, of the total association accounted for by body size), while the most recent adult obesity status (ages 33-39) is important for both of these gene expression signatures (24.3% and 35.1%, respectively). Body size in all life stages was associated with inflammation, consistent with the accumulation model.

College completion predicts lower depression but higher metabolic syndrome among disadvantaged minorities in young adulthood.

Individuals with higher educational attainment live healthier and longer lives. However, not everyone benefits equally from higher education. In particular, the black-white gap in life expectancy is greater at higher levels of educational attainment. Furthermore, recent research suggests that disadvantaged African Americans in the rural Southeast who attend college have worse physical health than their similarly disadvantaged peers who do not attend college. The extent to which this pattern generalizes to a nationally representative, mixed-race sample is unknown. Using data from the National Longitudinal Study of Adolescent to Adult Health, we test whether the health benefits associated with college completion vary by level of childhood disadvantage for depression and metabolic syndrome in young adulthood, across race/ethnicity. We find uniform lower depression associated with college completion regardless of childhood disadvantage, and across non-Hispanic white, non-Hispanic black, and Hispanic young adults. College completion is associated with lower metabolic syndrome for whites across all levels of childhood disadvantage. In contrast, college completion is associated with higher metabolic syndrome among black and Hispanic young adults from disadvantaged childhood environments. Our findings suggest that, for minorities from disadvantaged backgrounds, finishing college pays substantial dividends for mental health but simultaneously exacts costs with regard to physical health. This pattern contrasts starkly with whites and minorities from more privileged backgrounds, for whom college completion is associated with benefits to both mental and physical health. These results suggest that racial disparities in health may persist in part because the health of upwardly mobile minorities is compromised in young adulthood.

The social genome of friends and schoolmates in the National Longitudinal Study of Adolescent to Adult Health.

Humans tend to form social relationships with others who resemble them. Whether this sorting of like with like arises from historical patterns of migration, meso-level social structures in modern society, or individual-level selection of similar peers remains unsettled. Recent research has evaluated the possibility that unobserved genotypes may play an important role in the creation of homophilous relationships. We extend this work by using data from 5,500 adolescents from the National Longitudinal Study of Adolescent to Adult Health (Add Health) to examine genetic similarities among pairs of friends. Although there is some evidence that friends have correlated genotypes, both at the whole-genome level as well as at trait-associated loci (via polygenic scores), further analysis suggests that meso-level forces, such as school assignment, are a principal source of genetic similarity between friends. We also observe apparent social-genetic effects in which polygenic scores of an individual's friends and schoolmates predict the individual's own educational attainment. In contrast, an individual's height is unassociated with the height genetics of peers.

Genetic analysis of social-class mobility in five longitudinal studies.

A summary genetic measure, called a "polygenic score," derived from a genome-wide association study (GWAS) of education can modestly predict a person's educational and economic success. This prediction could signal a biological mechanism: Education-linked genetics could encode characteristics that help people get ahead in life. Alternatively, prediction could reflect social history: People from well-off families might stay well-off for social reasons, and these families might also look alike genetically. A key test to distinguish biological mechanism from social history is if people with higher education polygenic scores tend to climb the social ladder beyond their parents' position. Upward mobility would indicate education-linked genetics encodes characteristics that foster success. We tested if education-linked polygenic scores predicted social mobility in >20,000 individuals in five longitudinal studies in the United States, Britain, and New Zealand. Participants with higher polygenic scores achieved more education and career success and accumulated more wealth. However, they also tended to come from better-off families. In the key test, participants with higher polygenic scores tended to be upwardly mobile compared with their parents. Moreover, in sibling-difference analysis, the sibling with the higher polygenic score was more upwardly mobile. Thus, education GWAS discoveries are not mere correlates of privilege; they influence social mobility within a life. Additional analyses revealed that a mother's polygenic score predicted her child's attainment over and above the child's own polygenic score, suggesting parents' genetics can also affect their children's attainment through environmental pathways. Education GWAS discoveries affect socioeconomic attainment through influence on individuals' family-of-origin environments and their social mobility.

Not a family matter: The effects of religiosity on academic outcomes based on evidence from siblings.

Religiosity has been positively linked with multiple measures of academic success, but it is unclear whether the "effect" of religiosity on academic outcomes is causal or spurious. One source of heterogeneity that may contribute to a child's level of religiosity and his/her academic success is family background. This paper is the first to use sibling differences to estimate the associations between religiosity on short and long-term academic success. Our analysis yields two main results. First, more religious adolescents earned higher GPAs in high school, even after including family fixed effects. Second, because they earned higher GPAs in high school, more religious adolescents completed more years of education 14 years after their religiosity was measured. Our findings suggest that adolescents' religious commitments influence their schooling in both the short and long term and should be more actively included and theorized as important drivers of educational and economic stratification.

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

In the original paper, we used the variable "URBRUR08," from the 2008 survey wave as a measure of childhood urbanicity. Upon further investigation we realized that this variable actually measured Beale urban-rural code during the respondent's adulthood.  Thus, we reran our analysis of the pseudo-heritability of childhood urbanicity using the variable. The original results hold such that even with the first 20 principal components held constant, childhood urban-rural status appears to be ~20% "heritable" in GREML models-a figure that is actually higher than the original estimate reported in the paper (14% controlling for 25 PCs, 15% controlling for 10 PCs, and 29% controlling for two PCs). Meanwhile, the heritabilities of the other phenotypes-height, BMI and education-still do not change when they are residualized on childhood urbanicity. In other words, the original results of the paper do not change.

The Depths of Despair Among US Adults Entering Midlife.

OBJECTIVES: To test whether indicators of despair are rising among US adults as they age toward midlife and whether this rise is concentrated among low-educated Whites and in rural areas. METHODS: We used data from the National Longitudinal Study of Adolescent to Adult Health, a nationally representative study of US adolescents in 1994. Our sample was restricted to individuals who participated in 1 or more of 5 waves (1994-2017) and self-identified as non-Hispanic White, non-Hispanic Black, or Hispanic (n = 18 446). We examined change in indicators of despair from adolescence to adulthood using multilevel regression analysis, testing for differences by race/ethnicity, education, and rurality. RESULTS: We found evidence of rising despair among this cohort over the past decade. This increase was not restricted to low-educated Whites or to rural areas. CONCLUSIONS: Results suggest that generally rising despair among the young adult cohort now reaching midlife that cuts across racial/ethnic, educational, and geographic groups may presage rising midlife mortality for these subgroups in the next decade.

Does Despair Really Kill? A Roadmap for an Evidence-Based Answer.

Two seemingly associated demographic trends have generated considerable interest: income stagnation and rising premature mortality from suicides, drug poisoning, and alcoholic liver disease among US non-Hispanic Whites with low education. Economists interpret these population-level trends to indicate that despair induced by financial stressors is a shared pathway to these causes of death. Although we now have the catchy term "deaths of despair," we have yet to study its central empirical claim: that conceptually defined and empirically assessed "despair" is indeed a common pathway to several causes of death. At the level of the person, despair consists of cognitive, emotional, behavioral, and biological domains. Despair can also permeate social relationships, networks, institutions, and communities. Extant longitudinal data sets feature repeated measures of despair-before, during, and after the Great Recession-offering resources to test the role that despair induced by economic decline plays in premature morbidity and mortality. Such tests must also focus on protective factors that could shield individuals. Deaths of despair is more than a phrase; it constitutes a hypothesis that deserves conceptual mapping and empirical study with longitudinal, multilevel data.

New Evidence of Skin Color Bias and Health Outcomes Using Sibling Difference Models: A Research Note.

In this research note, we use data from the National Longitudinal Study of Adolescent to Adult Health (Add Health) to determine whether darker skin tone predicts hypertension among siblings using a family fixed-effects analytic strategy. We find that even after we account for common family background and home environment, body mass index, age, sex, and outdoor activity, darker skin color significantly predicts hypertension incidence among siblings. In a supplementary analysis using newly released genetic data from Add Health, we find no evidence that our results are biased by genetic pleiotropy, whereby differences in alleles among siblings relate to coloration and directly to cardiovascular health simultaneously. These results add to the extant evidence on color biases that are distinct from those based on race alone and that will likely only heighten in importance in an increasingly multiracial environment as categorization becomes more complex.

Social relationships and physiological determinants of longevity across the human life span.

Two decades of research indicate causal associations between social relationships and mortality, but important questions remain as to how social relationships affect health, when effects emerge, and how long they last. Drawing on data from four nationally representative longitudinal samples of the US population, we implemented an innovative life course design to assess the prospective association of both structural and functional dimensions of social relationships (social integration, social support, and social strain) with objectively measured biomarkers of physical health (C-reactive protein, systolic and diastolic blood pressure, waist circumference, and body mass index) within each life stage, including adolescence and young, middle, and late adulthood, and compare such associations across life stages. We found that a higher degree of social integration was associated with lower risk of physiological dysregulation in a dose-response manner in both early and later life. Conversely, lack of social connections was associated with vastly elevated risk in specific life stages. For example, social isolation increased the risk of inflammation by the same magnitude as physical inactivity in adolescence, and the effect of social isolation on hypertension exceeded that of clinical risk factors such as diabetes in old age. Analyses of multiple dimensions of social relationships within multiple samples across the life course produced consistent and robust associations with health. Physiological impacts of structural and functional dimensions of social relationships emerge uniquely in adolescence and midlife and persist into old age.

Father Absence and Accelerated Reproductive Development in Non-Hispanic White Women in the United States.

Girls who experience father absence in childhood also experience accelerated reproductive development in comparison with peers with present fathers. One hypothesis advanced to explain this empirical pattern is genetic confounding, wherein gene-environment correlation (rGE) causes a spurious relationship between father absence and reproductive timing. We test this hypothesis by constructing polygenic scores for age at menarche and first birth using recently available genome-wide association study results and molecular genetic data on a sample of non-Hispanic white females from the National Longitudinal Study of Adolescent to Adult Health. We find that young women's accelerated menarche polygenic scores are unrelated to their exposure to father absence. In contrast, polygenic scores for earlier age at first birth tend to be higher in young women raised in homes with absent fathers. Nevertheless, father absence and the polygenic scores independently and additively predict reproductive timing. We find no evidence in support of the rGE hypothesis for accelerated menarche and only limited evidence in support of the rGE hypothesis for earlier age at first birth.