Modeling Interaction and Dispersion Effects in the Analysis of Gene-by-Environment Interaction.

Genotype-by-environment interaction (GxE) studies probe heterogeneity in response to risk factors or interventions. Popular methods for estimation of GxE examine multiplicative interactions between individual genetic and environmental measures. However, risk factors and interventions may modulate the total variance of an epidemiological outcome that itself represents the aggregation of many other etiological components. We expand the traditional GxE model to directly model genetic and environmental moderation of the dispersion of the outcome. We derive a test statistic, [Formula: see text], for inferring whether an interaction identified between individual genetic and environmental measures represents a more general pattern of moderation of the total variance in the phenotype by either the genetic or the environmental measure. We validate our method via extensive simulation, and apply it to investigate genotype-by-birth year interactions for Body Mass Index (BMI) with polygenic scores in the Health and Retirement Study (N = 11,586) and individual genetic variants in the UK Biobank (N = 380,605). We find that changes in the penetrance of a genome-wide polygenic score for BMI across birth year are partly representative of a more general pattern of expanding BMI variation across generations. Three individual variants found to be more strongly associated with BMI among later born individuals, were also associated with the magnitude of variability in BMI itself within any given birth year, suggesting that they may confer general sensitivity of BMI to a range of unmeasured factors beyond those captured by birth year. We introduce an expanded GxE regression model that explicitly models genetic and environmental moderation of the dispersion of the outcome under study. This approach can determine whether GxE interactions identified are specific to the measured predictors or represent a more general pattern of moderation of the total variance in the outcome by the genetic and environmental measures.

Customizing CAT Administration of the PROMIS Misuse of Prescription Pain Medication Item Bank for Patients with Chronic Pain.

OBJECTIVE: The 22-item PROMIS®-Rx Pain Medication Misuse item bank (Bank-22) imposes a high response burden. This study aimed to characterize the performance of the Bank-22 in a computer adaptive testing (CAT) setting based on varied stopping rules. METHODS: The 22 items were administered to 288 patients. We performed a CAT simulation using default stopping rules (CATPROMIS). In 5 other simulations, a "best health" response rule was added to decrease response burden. This rule stopped CAT administration when a participant selected "never" to a specified number of initial Bank-22 items (2-6 in this study, designated CATAlt2-Alt6). The Bank-22 and 7-item short form (SF-7) scores were compared to scores based on CATPROMIS, and the 5 CAT variations. RESULTS: Bank-22 scores correlated highly with the SF-7 and CATPROMIS, Alt5, Alt6 scores (r=0.87-0.95) and moderately with CATAlt2- Alt4 scores (r=0.63-0.74). In all CAT conditions, the greatest differences with Bank-22 scores were at the lower end of misuse T-scores. The smallest differences with Bank-22 and CATPROMIS scores were observed with CATAlt5 and CATAlt6. Compared to the SF-7, CATAlt5 and CATAlt6 reduced overall response burden by about 42%. Finally, the correlations between PROMIS-Rx Misuse and Anxiety T-scores remained relatively unchanged across the conditions (r=0.31-0.43, Ps < .001). CONCLUSIONS: Applying a stopping rule based on number of initial "best health" responses reduced response burden for respondents with lower levels of misuse. The tradeoff was less measurement precision for those individuals, which could be an acceptable tradeoff when the chief concern is in discriminating higher levels of misuse.

Young Children's Prosocial Behavior Protects Against Academic Risk in Neighborhoods With Low Socioeconomic Status.

Children raised in neighborhoods with low socioeconomic status (SES) are at risk for low academic achievement. Identifying factors that help children from disadvantaged neighborhoods thrive is critical for reducing inequalities. We investigated whether children's prosocial behavior buffers concurrent and subsequent academic risk in disadvantaged neighborhoods in Bradford, UK. Diverse children (N = 1,175) were followed until age seven, with measurements taken at four times. We used governmental indices of neighborhood-level SES, teacher observations of prosocial behaviors, and direct assessments of academic achievement. Neighborhood SES was positively associated with academic achievement among children with low levels of prosocial behavior, but not among children with high levels of prosocial behavior. Prosocial behavior may mitigate academic risk across early childhood.

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.

Gender norms and health: insights from global survey data.

Despite global commitments to achieving gender equality and improving health and wellbeing for all, quantitative data and methods to precisely estimate the effect of gender norms on health inequities are underdeveloped. Nonetheless, existing global, national, and subnational data provide some key opportunities for testing associations between gender norms and health. Using innovative approaches to analysing proxies for gender norms, we generated evidence that gender norms impact the health of women and men across life stages, health sectors, and world regions. Six case studies showed that: (1) gender norms are complex and can intersect with other social factors to impact health over the life course; (2) early gender-normative influences by parents and peers can have multiple and differing health consequences for girls and boys; (3) non-conformity with, and transgression of, gender norms can be harmful to health, particularly when they trigger negative sanctions; and (4) the impact of gender norms on health can be context-specific, demanding care when designing effective gender-transformative health policies and programmes. Limitations of survey-based data are described that resulted in missed opportunities for investigating certain populations and domains. Recommendations for optimising and advancing research on the health impacts of gender norms are made.

The Earliest Origins of Genetic Nurture: The Prenatal Environment Mediates the Association Between Maternal Genetics and Child Development.

Observed genetic associations with educational attainment may be due to direct or indirect genetic influences. Recent work highlights genetic nurture, the potential effect of parents' genetics on their child's educational outcomes via rearing environments. To date, few mediating childhood environments have been tested. We used a large sample of genotyped mother-child dyads (N = 2,077) to investigate whether genetic nurture occurs via the prenatal environment. We found that mothers with more education-related genes are generally healthier and more financially stable during pregnancy. Further, measured prenatal conditions explain up to one third of the associations between maternal genetics and children's academic and developmental outcomes at the ages of 4 to 7 years. By providing the first evidence of prenatal genetic nurture and showing that genetic nurture is detectable in early childhood, this study broadens our understanding of how parental genetics may influence children and illustrates the challenges of within-person interpretation of existing genetic associations.

Separating Measured Genetic and Environmental Effects: Evidence Linking Parental Genotype and Adopted Child Outcomes.

There has been widespread adoption of genome wide summary scores (polygenic scores) as tools for studying the importance of genetics and associated life course mechanisms across a range of demographic and socioeconomic outcomes. However, an often unacknowledged issue with these studies is that parental genetics impact both child environments and child genetics, leaving the effects of polygenic scores difficult to interpret. This paper uses multi-generational data containing polygenic scores for parents (n = 7193) and educational outcomes for adopted (n = 855) and biological (n = 20,939) children, many raised in the same families, which allows us to separate the influence of parental polygenic scores on children outcomes between environmental (adopted children) and environmental and genetic (biological children) effects. Our results complement recent work on "genetic nurture" by showing associations of parental polygenic scores with adopted children's schooling, providing additional evidence that polygenic scores combine genetic and environmental influences and that research designs are needed to separate these estimated impacts.

Sleep-wake disorders in Alzheimer's disease: further genetic analyses in relation to objective sleep measures.

This paper presents updated analyses on the genetic associations of sleep disruption in individuals with Alzheimer's disease (AD). We published previously a study of the association between single nucleotide polymorphisms (SNPs) found in eight genes related to circadian rhythms and objective measures of sleep-wake disturbances in 124 individuals with AD. Here, we present new relevant analyses using polygenic risk scores (PRS) and variable number tandem repeats (VNTRs) enumerations. PRS were calculated using the genetic data from the original participants and relevant genome wide association studies (GWAS). VNTRs for the same circadian rhythm genes studied with SNPs were obtained from a separate cohort of participants using whole genome sequencing (WGS). Objectively (wrist actigraphy) determined wake after sleep onset (WASO) was used as a measure of sleep disruption. None of the PRS were associated with sleep disturbance. Computer analyses using VNTRseek software generated a total of 30 VNTRs for the circadian-related genes but none appear relevant to our objective sleep measure. In addition, of 71 neurotransmitter function-related genes, 29 genes had VNTRs that differed from the reference VNTR, but it was not clear if any of these might affect circadian function in AD patients. Although we have not found in either the current analyses or in our previous published analyses of SNPs any direct linkages between identified genetic factors and WASO, research in this area remains in its infancy.

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.

Genetic risk, body mass index, and weight control behaviors: Unlocking the triad.

BACKGROUND: The relationship between genetic risk for body mass index (BMI) and weight control behaviors remains unknown. The objectives of this study were to determine the association between genetic risk for BMI and weight control behaviors in young adults, and to examine actual measured BMI as a potential mediator variable. METHOD: We analyzed data from three data collection waves of the National Longitudinal Study of Adolescent to Adult Health. The BMI polygenic score (PGS) was based on published genome-wide association studies for BMI. BMI was collected at 11-18 years and 18-26 years. Weight control behaviors included self-reported: (a) weight loss behaviors (dieting, vomiting, fasting/skipping meals, diet pills, laxatives, or diuretic use to lose weight) and (b) weight gain behaviors (eating more or different foods than normal, taking supplements to gain weight). RESULTS: Among 4,397 participants, the BMI PGS was associated with higher odds of weight loss behaviors in females (OR 1.24, 95% CI 1.14-1.35) and males (OR 1.43, 95% CI 1.26-1.62), and this association was mediated by BMI (indirect effect 0.04, 95% CI 0.03-0.05 in females and 0.03, 95% CI 0.03-0.04 in males). The BMI PGS was associated with lower odds of weight gain behaviors in females and males, which was also mediated by actual BMI. CONCLUSIONS: The BMI PGS was associated with weight loss behaviors in both males and females, and this association was mediated by actual measured BMI. Clinical interventions to prevent high BMI, particularly for individuals with genetic risk, may also prevent subsequent development of potentially unhealthy weight loss behaviors.

Assortative mating and differential fertility by phenotype and genotype across the 20th century.

This study asks two related questions about the shifting landscape of marriage and reproduction in US society over the course of the last century with respect to a range of health and behavioral phenotypes and their associated genetic architecture: (i) Has assortment on measured genetic factors influencing reproductive and social fitness traits changed over the course of the 20th century? (ii) Has the genetic covariance between fitness (as measured by total fertility) and other traits changed over time? The answers to these questions inform our understanding of how the genetic landscape of American society has changed over the past century and have implications for population trends. We show that husbands and wives carry similar loadings for genetic factors related to education and height. However, the magnitude of this similarity is modest and has been fairly consistent over the course of the 20th century. This consistency is particularly notable in the case of education, for which phenotypic similarity among spouses has increased in recent years. Likewise, changing patterns of the number of children ever born by phenotype are not matched by shifts in genotype-fertility relationships over time. Taken together, these trends provide no evidence that social sorting is becoming increasingly genetic in nature or that dysgenic dynamics have accelerated.

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.

Education, Smoking, and Cohort Change: Forwarding a Multidimensional Theory of the Environmental Moderation of Genetic Effects.

We introduce a genetic correlation by environment interaction model [(rG)xE] which allows for social environmental moderation of the genetic relationship between two traits. To empirically demonstrate the significance of the (rG)xE perspective, we use genome wide information from respondents of the Health and Retirement Study (HRS; n = 8,181; birth years 1920-1959) and the National Longitudinal Study of Adolescent to Adult Health (Add Health; n = 4,347; birth years 1974-1983) to examine whether the genetic correlation (rG) between education and smoking has increased over historical time. Genetic correlation estimates (rGHRS = -0.357; rGAdd Health = -0.729) support this hypothesis. Using polygenic scores for educational attainment, we show that this is not due to latent indicators of intellectual capacity, and we highlight the importance of education itself as an explanation of the increasing genetic correlation. Analyses based on contextual variation the milieus of the Add Health respondents corroborate key elements of the birth cohort analyses. We argue that the increasing overlap with respect to genes associated with educational attainment and smoking is a fundamentally social process involving complex process of selection based on observable behaviors that may be linked to genotype.

Genetic and educational assortative mating among US adults.

Understanding the social and biological mechanisms that lead to homogamy (similar individuals marrying one another) has been a long-standing issue across many fields of scientific inquiry. Using a nationally representative sample of non-Hispanic white US adults from the Health and Retirement Study and information from 1.7 million single-nucleotide polymorphisms, we compare genetic similarity among married couples to noncoupled pairs in the population. We provide evidence for genetic assortative mating in this population but the strength of this association is substantially smaller than the strength of educational assortative mating in the same sample. Furthermore, genetic similarity explains at most 10% of the assortative mating by education levels. Results are replicated using comparable data from the Framingham Heart Study.

Cohort Effects in the Genetic Influence on Smoking.

We examine the hypothesis that the heritability of smoking has varied over the course of recent history as a function of associated changes in the composition of the smoking and non-smoking populations. Classical twin-based heritability analysis has suggested that genetic basis of smoking has increased as the information about the harms of tobacco has become more prevalent-particularly after the issuance of the 1964 Surgeon General's Report. In the present paper we deploy alternative methods to test this claim. We use data from the Health and Retirement Study to estimate cohort differences in the genetic influence on smoking using both genomic-relatedness-matrix restricted maximum likelihood and a modified DeFries-Fulker approach. We perform a similar exercise deploying a polygenic score for smoking using results generated by the Tobacco and Genetics consortium. The results support earlier claims that the genetic influence in smoking behavior has increased over time. Emphasizing historical periods and birth cohorts as environmental factors has benefits over existing GxE research. Our results provide additional support for the idea that anti-smoking policies of the 1980s may not be as effective because of the increasingly important role of genotype as a determinant of smoking status.

The National Longitudinal Study of Adolescent to Adult Health (Add Health) sibling pairs genome-wide data.

Here we provide a detailed description of the genome-wide information available on the National Longitudinal Study of Adolescent to Adult Health (Add Health) sibling pair subsample (Harris et al. in Twin Res Hum Genet 16:391-398, 2013). A total of 2,020 samples were genotyped (including duplicates) arising from 1946 Add Health individuals from the sibling pairs subsample. After various steps for quality control (QC) and quality assurance (QA), we have high quality genome-wide data available on 1,888 individuals. In this report, we first highlight the QC and QA steps that were taken to prune the data of poorly performing samples and genetic markers. We further estimate the pairwise biological relationships using genome-wide data and compare those estimates to the assumed relationships in Add Health. Additionally, using genome-wide data from known regional reference populations from Europe, West Africa, North and South America, Japan and China, we estimate the relative genetic ancestry of the respondents. Finally, rather than conducting a traditional cross-sectional genome-wide association study (GWAS) of body mass index (BMI), we opted to utilize the extensive publicly available genome-wide information to conduct a weighted GWAS of longitudinal BMI while accounting for both family and ethnic variation.

Breastfeeding is associated with waist-to-height ratio in young adults.

BACKGROUND: The current study investigated the association between breastfeeding and adult weight distribution using an emerging indicator of weight distribution, the waist-to-height ratio (WHtR). METHODS: The study sample consisted of two subsamples of individuals that were part of the National Longitudinal Study of Adolescent Health. One sample (n = 1,179) consisted of individuals from the sibling pair data. A second sample (n = 4,648) consisted of individuals that were not part of the paired data. Regression models were constructed to establish if there was a relationship between breastfeeding and two measures of weight distribution: WHtR and body mass index (BMI). Controls for parental socioeconomic status, maternal smoking, race, sex, age, birth weight, maternal BMI, genetic ancestry, and a genetic risk score (GRS) for obesity were included. In addition, a behavioral risk score (BRS) was constructed to control for other residual confounding factors. RESULTS: A significant, inverse relationship between breastfeeding and adult WHtR persisted in models constructed from the sibling pair sample (P = 0.002) and unrelated sample (P < 0.0001). This association remained significant with the inclusion of ancestry principal components, GRS, and a measure of maternal obesity. CONCLUSIONS: The moderate association between breastfeeding and weight distribution persists into adulthood while controlling for potential confounders. This paper also provides evidence that the WHtR may be a superior outcome measure to BMI in studies investigating breastfeeding and obesity.