Pathways between a polygenic index for education and years of completed schooling: the presentation of self and assessment of others.

Polygenic scores (PGS) are broadly misconstrued as reflecting direct causal genetic effects on their respective phenotypes. While this assumption might be accurate for some anthropometric traits like height, more complex traits such as educational attainment show very large indirect effects that stem from many sources. One unexplored source of confounding is the possibility of evocative gene-environment correlation (rGE). Using data from the National Longitudinal Study of Adolescent to Adult Health, we examine the relationship between interviewer assessments of respondent appearance as a function of education PGS. We show a bivariate association between educational PGS and 1) perceived grooming, 2) physical attractiveness, and 3) personality. We then regress years of education on the educational PGS and show that very little of the association (~1-2%) is mediated by attractiveness or personality but 7.5% of the baseline association is confounded with how others may perceive grooming. These results highlight the importance of social-behavioral mechanisms that may link specific genotypes to successful transitions through high school and college and continue to bridge research from the social and biological sciences.

Parental imprisonment, delinquent behavior, and BMI gain in a U.S. nationally representative cohort study of adolescents and adults ages 12-32.

Children who experience parental imprisonment report greater mental and physical health adversities in adolescence and adulthood relative to comparable individuals whose parents did not serve time in prison. Research has linked BMI gain with parental imprisonment among females, but other studies have shown null or negative associations between parental imprisonment and weight increases for their offspring. Using longitudinal data from the National Longitudinal Study of Adolescent to Adult Health, this study attempts to resolve these differential findings by examining the interrelationship between delinquent behavior and BMI associated with parental imprisonment as individuals progress from adolescence into adulthood (ages 12-32). We show that higher delinquency levels are associated with lower BMI among men and women. With the transition from adolescence to adulthood, parental imprisonment is linked with increased BMI gain and obesity among females who are not delinquent. These findings highlight the need to consider how the decline in delinquent behavior and increasing health disparities between adolescence and adulthood may intersect as individuals experiencing parental imprisonment transition from adolescence to adulthood.

Cognition and Diabetes: Examining Sex Differences Using a Longitudinal Sample of Older Adults.

Objectives: This study aims to investigate sex-based differences in the diabetes status and cognition relationship using a representative sample of older Americans. Methods: Using a sample of 19,190 females and 15,580 males from the Health and Retirement Study, we conduct mixed-effects linear regression analyses to examine sex differences in the association between diabetes and cognition over a 20-year follow-up period among older adults in the United States. Main Findings: Females experience slightly steeper declines in cognition that are further exacerbated by diabetes. At age 65, females without diabetes have significantly higher cognition than males; this gap is eliminated by age 85. Among diabetics, there is no initial sex disparity, but females' cognition becomes significantly lower than males' over the following 20 years. Principal Conclusions: Relative to males, females are particularly susceptible to diabetes-related declines in cognition with increasing age.

Genetic diversity fuels gene discovery for tobacco and alcohol use.

Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury1-4. These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries5. Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction.

Does crime trigger genetic risk for type 2 diabetes in young adults? A G x E interaction study using national data.

BACKGROUND: Living in neighborhoods perceived as disordered exacerbates genetic risk for type 2 diabetes (T2D) among older adults. It is unknown whether this gene-neighborhood interaction extends to younger adults. The present study aims to investigate whether crime, an objectively measured indicator of neighborhood disorder, triggers genetic risk for T2D among younger adults, and whether this hypothesized triggering occurs through exposure to obesity. METHODS: Data were from the Wave I (2008) National Longitudinal Study of Adolescent to Adult Health. A standardized T2D polygenic score was created using 2014 GWAS meta-analysis results. Weighted mediation analyses using generalized structural equation models were conducted in a final sample of 7606 adults (age range: 25-34) to test the overall association of T2D polygenic scores with T2D, and the mediating path through obesity exposure in low, moderate, and high county crime-rate groups. Age, sex, ancestry, educational degree, household income, five genetic principal components, and county-level concentrated advantage and population density were adjusted. RESULTS: The overall association between T2D polygenic score and T2D was not significant in low-crime areas (p = 0.453), marginally significant in moderate-crime areas (p = 0.064), and statistically significant in high-crime areas (p = 0.007). The mediating path through obesity was not significant in low or moderate crime areas (ps = 0.560 and 0.261, respectively), but was statistically significant in high-crime areas (p = 0.023). The indirect path through obesity accounted for 12% of the overall association in high-crime area. CONCLUSION: A gene-crime interaction in T2D was observed among younger adults, and this association was partially explained by exposure to obesity.

Exploring Rural-Urban Differences in Polygenic Associations for Health among Older Adults in the United States.

This paper contributes to research on health disparities among rural and urban residents by considering differences in the magnitude of genetic associations for physical health, mental health, and health behaviors across the two settings. Previous research has shown reduced genetic associations in rural compared to urban settings but none have utilized current genome-wide polygenic scores and none have focused on older adults. Using a sample of 14,994 adults from the 1992 to 2016 waves of the Health and Retirement Study our results suggest genetic associations for BMI (p<.018) and heart conditions (p < .023) are significantly reduced in rural compared to urban settings and we find weak evidence in support of this association for depression (p. < .065) and no evidence for smoking (p < 461). In sum, the weaker genetic associations in rural areas highlights the centrality of the social, economic, and built environment as a determinant of disparities.

Genome-wide stress sensitivity moderates the stress-depression relationship in a nationally representative sample of adults.

We re-evaluate the findings of one of the most cited and disputed papers in gene-environment interaction (GxE) literature. In 2003, a paper was published in Science in which the authors demonstrated that the relationship between stress and depression is moderated by a polymorphism in the promoter region (5-HTTLPR) of the gene SLC6A4. Replication has been weak and led many to challenge the overall significance of GxE research. Here, we utilize data from Add Health, a large, nationally representative, and well-powered longitudinal study to re-examine the genetic determinants of stress sensitivity. We characterize environmental sensitivity using a genome-wide polygenic indicator rather than relying on one polymorphism in a single candidate gene. Our results provide support for the stress-diathesis perspective and validate the scientific contributions of the original paper.

Evaluating the Continued Integration of Genetics into Medical Sociology.

The 2010 special issue of Journal of Health and Social Behavior, titled "Fifty Years of Medical Sociology," defined the contours of the medical sociological perspective. We use this as a backdrop to outline and assess the continued integration of genetics into medical sociology research. We contend that the explosion of genetic and epigenetic data in population health data sources has made the medical sociological perspective increasingly relevant to researchers outside of sociology, including public health, epidemiology, and quantitative genetics. We describe vast, underappreciated, and mostly unsolved challenges that limit the scientifically appropriate interest in incorporating genetics into existing paradigms. It is our hope that medical sociologists continue this integration but redouble efforts to maintain the core insights in social science research, such as the importance of environmental and structural (i.e., nonbiological) factors in determining health processes and outcomes and the use of rich, integrated, and rigorous empirical analyses.

Cognition in context: Pathways and compound risk in a sample of US non-Hispanic whites.

The population of individuals with cognitive impairment and dementia is growing rapidly, necessitating etiological investigation. It is clear that individual differences in cognition later in life have both genetic and multi-level environmental correlates. Despite significant recent progress in cellular and molecular research, the exact mechanisms linking genes, brains, and cognition remain elusive. In relation to cognition, it is unlikely that genetic and environmental risk factors function in a vacuum, but rather interact and cluster together. The purpose of the present study was to examine whether aspects of individual socioeconomic status (SES) explain the cognitive genotype-phenotype association, and whether neighborhood SES modifies the effects of genes and individual SES on cognitive ability. Using data from non-Hispanic White participants in the 2016 wave of the Health and Retirement Study, a national sample of United States adults, we examined links between a polygenic score for general cognition and performance-based cognitive functioning. In a series of weighted linear regressions and formal tests of mediation, we observed a significant genotype-phenotype association that was partially attenuated after including individual education to the baseline model, although little reductions were observed for household wealth or census tract-level percent poverty. These findings suggest that genetic risk for poor cognition is partially explained by education, and this pathway is not modified by poverty-level of the neighborhood.

Utilizing genome wide data to highlight the social behavioral pathways to health: The case of obesity and cardiovascular health among older adults.

We use genome-wide data from the 1992-2016 Health and Retirement Study (n = 12,090) to characterize obesity among older adults as genetically or socially oriented. To illustrate the significance of this approach for social epidemiological research, we deem those with the lowest genetic risk for obesity to be socially-behaviorally obese and obesity among those with the highest polygenic risk is characterized as genetically oriented. We then examine the association between obesity and four indicators of cardiovascular health (type-2 diabetes, hypertension, heart problems, and stroke) among those with low, average, and high genetic risk. Our results show that the association between obesity and cardiovascular health is significantly higher for those with the lowest genetic risk (e.g., social-behavioral obesity). We also demonstrate important sex differences such that this association is particularly strong for heart problems among men and hypertension and stroke among women. Our results further demonstrate the centrality of the social and behavioral determinants of health by utilizing detailed information across the human genome and add to both social and genetic epidemiology literatures.

Mortality and Obesity Among U.S. Older Adults: The Role of Polygenic Risk.

OBJECTIVES: To examine the relationship between obesity and mortality as a function of polygenic risk for obesity among older U.S. adults. METHOD: Using data from the 1994-2014 Health and Retirement Study in conjunction with genome-wide data, we evaluated the risk of mortality as a function of obesity classification, an individual's polygenic risk score (PGS) for obesity, and their interaction, stratified by sex. We conducted our analyses using cox proportional hazard models. RESULTS: Among those with an average PGS for obesity (8,143 [68.8%]), obese I (hazard ratio [HR] = 0.79, p = .336) adults show no difference in their risk for mortality and obese II/III (HR = 3.17, p = .000) adults present higher risk of mortality relative to non-obese adults. The interaction of obesity classification and PGS suggests that obese II/III respondents with low PGS in the total sample (HR = 2.71, p = .006) and among women (HR = 3.02, p = .023) are at significantly higher risk of death when compared to obese II/III respondents with average or high PGS. DISCUSSION: We posit that these findings suggest that the pathway to obesity, in this case, more socio-behavioral rather than genetic, may influence subsequent risk of death in older adults. We suggest that practitioners and population researchers be mindful of these pathways as to better identify and understand mortality risk.

Genes Related to Education Predict Frailty Among Older Adults in the United States.

OBJECTIVE: This article expands on research that links education and frailty among older adults by considering the role of genes associated with education. METHOD: Data come from a sample of 7,064 non-Hispanic, white adults participating in the 2004-2012 waves of the Health and Retirement Study. Frailty was measured with two indices: (a) The Frailty Index which corresponds to a deficit accumulation model; and (b) The Paulson-Lichtenberg Frailty Index which corresponds to the biological syndrome/phenotype model. Genes associated with education were quantified using an additive polygenic score. Associations between the polygenic score and frailty indices were tested using a series of multilevel models, controlling for multiple observations for participants across waves. RESULTS: Results showed a strong and negative association between genes for education and frailty symptoms in later life. This association exists above and beyond years of completed education and we demonstrate that this association becomes weaker as older adults approach their 80s. DISCUSSION: The results contribute to the education-health literature by highlighting new and important pathways through which education might be linked to successful aging.

Hearing Impairment, Household Composition, Marital Status, and Mortality Among U.S. Adults.

OBJECTIVES: This study investigates associations between hearing impairment, household composition, marital status, and all-cause mortality for a representative sample of United States adults aged 40 and older (N = 198,902). METHODS: We use data from 11 waves of the National Health Interview Survey (2004-2014) linked to prospective mortality status through 2015. The risk of mortality over the follow-up period is estimated using Cox proportional hazard models. RESULTS: Compared to those with good to excellent hearing, adults with moderate to severe hearing impairments and deaf adults had 11% and 21% higher risk of death from any cause over the follow-up period, respectively. Household composition and marital status, as indicators of household social support systems, associated independently with the risk of mortality but did not substantively change the association between hearing impairment and mortality. DISCUSSION: Hearing impairment represents an important contributor to the length of life for adults age 40 and older, independent of other important and established determinants of mortality.

A mutation associated with stress resistance in mice is associated with human grip strength and mortality.

Hand grip strength (GS) is a valid and reliable predictor of future morbidity and mortality and is considered a useful indicator of aging. In this paper, we use results from the genetic analysis in animal studies to evaluate associations for GS, frailty, and subsequent mortality among humans. Specifically, we use data from the Health and Retirement Survey (HRS) to investigate the association between three polymorphisms in a candidate frailty gene (Tiam1) and GS. Results suggest that the A allele in rs724561 significantly reduces GS among older adults in the US (b = -0.340; p < .006) and is significantly associated with self-reported weakness (b = 0.221; p = .036). This same polymorphism was weakly associated (one-tailed) with an increased risk of mortality (b = 1.091; p < .093) and adjustments for GS rendered this association statistically non-significant (b = 1.048; p < .361). Overall, our results provide tentative evidence that the Tiam1 gene may be associated with frailty development, but we encourage further studies.

Perceived neighborhood social cohesion and cardiometabolic risk: a gene × environment study.

People living in socially cohesive neighborhoods generally have better health. We extend this research by evaluating the hypothesis that perceived neighborhood cohesion may influence health by attenuating genetic liability for cardiometabolic risk factors. Using data from the Health and Retirement Study (n = 6615; mean age 69.7), we conducted a gene × environment interaction study hypothesizing that perceived neighborhood cohesion would attenuate the link between polygenic scores for waist-to-hip ratio (WHR) and body mass index and a measure of multisystem cardiometabolic risk (systolic and diastolic blood pressure, heart rate, A1c, C-reactive protein, and total and high-density lipoprotein cholesterol). In support of the hypothesis, results indicated that among people perceiving low neighborhood cohesion, higher WHR polygenic scores were associated with greater cardiometabolic risk. In contrast, the genetic-cardiometabolic risk link was much attenuated among those living in neighborhoods perceived as socially cohesive. Our results support community-level interventions to enhance the social cohesiveness of individuals' neighborhoods which may provide health benefits by reducing the risks associated with known genetic risk factors.

Genetic associations with mathematics tracking and persistence in secondary school.

Maximizing the flow of students through the science, technology, engineering, and math (STEM) pipeline is important to promoting human capital development and reducing economic inequality. A critical juncture in the STEM pipeline is the highly cumulative sequence of secondary school math courses. Students from disadvantaged schools are less likely to complete advanced math courses. Here, we conduct an analysis of how the math pipeline differs across schools using student polygenic scores, which are DNA-based indicators of propensity to succeed in education. We integrated genetic and official school transcript data from over 3000 European-ancestry students from U.S. high schools. We used polygenic scores as a molecular tracer to understand how the flow of students through the high school math pipeline differs in socioeconomically advantaged versus disadvantaged schools. Students with higher education polygenic scores were tracked to more advanced math already at the beginning of high school and persisted in math for more years. Analyses using genetics as a molecular tracer revealed that the dynamics of the math pipeline differed by school advantage. Compared to disadvantaged schools, advantaged schools buffered students with low polygenic scores from dropping out of math. Across all schools, even students with exceptional polygenic scores (top 2%) were unlikely to take the most advanced math classes, suggesting substantial room for improvement in the development of potential STEM talent. These results link new molecular genetic discoveries to a common target of educational-policy reforms.

Implications of gendered behaviour and contexts for social mobility in the USA: a nationally representative observational study.

BACKGROUND: We constructed measures of an individual's gendered behaviour and their gendered environment to investigate the salience of gender norms during adolescence for social mobility during the next decade of life. METHODS: In this nationally representative observational study, we collected individual-level data from the National Longitudinal Study of Adolescent to Adult Health (Add Health), which enrolled a cohort of nationally representative school students aged 11-19 years from across the USA and followed them up for 14 years (ie, to age 25-33 years). We characterised gendered behaviour for adolescents in a performative sense via self-reports of behaviours and beliefs. We aggregated this individual-level measure to create a proxy measure of an individual's social context by taking averages for an individual's peers of the same sex and school year. FINDINGS: Between Jan 5, 1994, and Dec 26, 1995, Add Health collected data on a cohort of 20 745 students. 14 540 respondents were followed-up 14 years later between April 3, 2007, and Feb 1, 2009, of whom 7722 (53·1%) were female. More masculine male respondents were downwardly mobile; they were enrolled in school for fewer years and were more likely to have lower status jobs than their less masculine same-sex school peers. More masculine male respondents were also more likely to have jobs in occupational categories with larger proportions of males than their same-sex school peers. Gendered behaviour was not predictive of future educational and occupational attainment for female respondents. Male adolescents in school years with more masculine same-sex peers than male adolescents in other school years also tended to have lower educational and occupational attainment than their male peers. Educational and occupational attainment in early midlife for female respondents was not affected by their gendered environment. INTERPRETATION: Gender, when measured as a set of gender-distinct behaviours in adolescence, was associated with differential patterns of social mobility from adolescence to young adulthood. Moreover, variation in an individual's local gender norms has implications for subsequent socioeconomic attainment, especially for male adolescents. These findings have potential implications for observed health disparities. FUNDING: Bill & Melinda Gates Foundation.

Association of Adolescent Sport Participation With Cognition and Depressive Symptoms in Early Adulthood.

BACKGROUND: Recent studies have associated sport-related concussion with depression and impaired cognitive ability later in life in former professional football players. However, population studies with two 1950s-era cohorts did not find an association between high school football participation and impaired cognition or depressive symptoms in late adulthood. PURPOSE/HYPOTHESIS: This study assessed whether actual/intended participation in contact sports during adolescence had an adverse effect on participants' cognition or depressive symptoms in early adulthood. We hypothesized that there would not be an association. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: This study used a subsample (n = 10,951) from the National Longitudinal Study of Adolescent to Adult Health (Add Health), a nationally (United States) representative prospective cohort study following participants through 4 waves of data collection from 1994 through 2008. Participants were categorized as actual/intended participation in no sports, noncontact sports only, and contact sports. We constructed 6 multivariate and logistic regression models predicting word recall, number recall, modified Center for Epidemiologic Studies Depression Scale, depression diagnosis, suicide ideation, and suicide attempts at wave IV as a function of sport participation during wave I. Sport participation was treated as a factor with the referent category noncontact sports. This analysis was repeated on a males-only sample (n = 5008). In the males-only analysis, participants were classified as actual/intended participation in no sports, noncontact sports, contact sports other than American football, and American football. The referent category remained noncontact sports. RESULTS: Intention to participate in contact sports was not significantly associated with any of the outcomes in the full-sample analysis. Intention to participate in football was significantly associated with a reduced odds of depression diagnosis in adulthood (odds ratio, 0.70; P = .02) when compared with noncontact sports participation in the males-only sample. Football was not significantly associated with impaired cognitive ability, increased depressive symptoms, or increased suicide ideation. CONCLUSION: Actual/intended participation in contact sports during adolescence did not adversely affect Add Health participants' cognition or depressive symptoms in young adulthood.

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.

Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use.

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders1. They are heritable2,3 and etiologically related4,5 behaviors that have been resistant to gene discovery efforts6-11. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures.