Exploring the Fetal Origins Hypothesis Using Genetic Data.

Birth weight is a robust predictor of valued life course outcomes, emphasizing the importance of prenatal development. But does birth weight act as a proxy for environmental conditions in utero, or do biological processes surrounding birth weight themselves play a role in healthy development? To answer this question, we leverage variation in birth weight that is, within families, orthogonal to prenatal environmental conditions: one's genes. We construct polygenic scores in two longitudinal studies (Born in Bradford, N = 2008; Wisconsin Longitudinal Study, N = 8488) to empirically explore the molecular genetic correlates of birth weight. A 1 standard deviation increase in the polygenic score is associated with an ~100-grams increase in birth weight and a 1.4 pp (22 percent) decrease in low birth weight probability. Sibling comparisons illustrate that this association largely represents a causal effect. The polygenic score-birth weight association is increased for children who spend longer in the womb and whose mothers have higher body mass index, though we find no differences across maternal socioeconomic status. Finally, the polygenic score affects social and cognitive outcomes, suggesting that birth weight is itself related to healthy prenatal development.

The Effects of the Flint water crisis on the educational outcomes of school-age children.

In 2014, the municipal water source in Flint, Michigan was switched, causing lead from aging pipes to leach into the city's drinking water. While lead exposure in Flint children increased modestly on average, some children were exposed to high lead levels. Surveys of Flint residents show the water crisis was also associated with increased levels of stress, anxiety, and depression. We use Michigan's administrative education data and utilize synthetic control methods to examine the impact of the crisis on Flint's school-age children. We find decreases in math achievement and increases in special needs classification, even among children living in homes with copper (rather than lead) water service lines. Low socioeconomic status students and younger students experienced the largest effects on math achievement, and boys experienced the largest effects on special needs classification. Our results point toward the broad negative effects of the crisis on children and suggest that existing estimates may substantially underestimate the overall societal cost of the crisis.

Beware of the phony horserace between genes and environments.

Although Burt provides a valuable critique of the scientific value of integrating genetic data into social science research, she reinforces rather than disrupts the age-old horserace between genetic effects and environmental effects. We must move past this false dichotomy to create a new ontology that recognizes the ways in which genetic and environmental processes are inextricably intertwined.

Ubiquitous bias and false discovery due to model misspecification in analysis of statistical interactions: The role of the outcome's distribution and metric properties.

Studies of interaction effects are of great interest because they identify crucial interplay between predictors in explaining outcomes. Previous work has considered several potential sources of statistical bias and substantive misinterpretation in the study of interactions, but less attention has been devoted to the role of the outcome variable in such research. Here, we consider bias and false discovery associated with estimates of interaction parameters as a function of the distributional and metric properties of the outcome variable. We begin by illustrating that, for a variety of noncontinuously distributed outcomes (i.e., binary and count outcomes), attempts to use the linear model for recovery leads to catastrophic levels of bias and false discovery. Next, focusing on transformations of normally distributed variables (i.e., censoring and noninterval scaling), we show that linear models again produce spurious interaction effects. We provide explanations offering geometric and algebraic intuition as to why interactions are a challenge for these incorrectly specified models. In light of these findings, we make two specific recommendations. First, a careful consideration of the outcome's distributional properties should be a standard component of interaction studies. Second, researchers should approach research focusing on interactions with heightened levels of scrutiny. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Ethical, anticipatory genomics research on human behavior means celebrating disagreement.

Despite the many social and ethical considerations in human genetics, researchers and communities remain largely siloed as for-profit, direct-to-consumer genetic testing and the application of polygenic scores to in vitro fertilization services become increasingly prevalent. The multifaceted challenges facing genomics, both empirical and ethical, require collaborations that foster critical dialogue and honest debate between communities inside and outside the research enterprise. This piece argues that in order to respond to the premature or inappropriate use of genomic data in industry, the scientific community needs to first embrace, understand, and be in dialogue about its disagreements. We introduce the research framework of adversarial collaboration as a way to celebrate disagreement and productively work toward policy-informed, ethical, and anticipatory genomics research.

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.

Local exposure to school shootings and youth antidepressant use.

While over 240,000 American students experienced a school shooting in the last two decades, little is known about the impacts of these events on the mental health of surviving youth. Using large-scale prescription data from 2006 to 2015, we examine the effects of 44 school shootings on youth antidepressant use. Our empirical strategy compares the number of antidepressant prescriptions written by providers practicing 0 to 5 miles from a school that experienced a shooting (treatment areas) to the number of prescriptions written by providers practicing 10 to 15 miles away (reference areas), both before and after the shooting. We include month-by-year and school-by-area fixed effects in all specifications, thereby controlling for overall trends in antidepressant use and all time-invariant differences across locations. We find that local exposure to fatal school shootings increases youth antidepressant use by 21.4% in the following 2 y. These effects are smaller in areas with a higher density of mental health providers who focus on behavioral, rather than pharmacological, interventions.

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.

Interactions between Polygenic Scores and Environments: Methodological and Conceptual Challenges.

Interest in the study of gene-environment interaction has recently grown due to the sudden availability of molecular genetic data-in particular, polygenic scores-in many long-running longitudinal studies. Identifying and estimating statistical interactions comes with several analytic and inferential challenges; these challenges are heightened when used to integrate observational genomic and social science data. We articulate some of these key challenges, provide new perspectives on the study of gene-environment interactions, and end by offering some practical guidance for conducting research in this area. Given the sudden availability of well-powered polygenic scores, we anticipate a substantial increase in research testing for interaction between such scores and environments. The issues we discuss, if not properly addressed, may impact the enduring scientific value of gene-environment interaction studies.

Schools as Moderators of Genetic Associations with Life Course Attainments: Evidence from the WLS and Add Health.

Genetic variants identified in genome-wide association studies of educational attainment have been linked with a range of positive life course development outcomes. However, it remains unclear whether school environments may moderate these genetic associations. We analyze data from two biosocial surveys that contain both genetic data and follow students from secondary school through mid- to late life. We test if the magnitudes of the associations with educational and occupational attainments varied across the secondary schools that participants attended or with characteristics of those schools. Although we find little evidence that genetic associations with educational and occupational attainment varied across schools or with school characteristics, genetic associations with any postsecondary education and college completion were moderated by school-level socioeconomic status. Along similar lines, we observe substantial between-school variation in the average level of educational attainment students achieved for a fixed genotype. These findings emphasize the importance of social context in the interpretation of genetic associations. Specifically, our results suggest that though existing measures of individual genetic endowment have a linear relationship with years of schooling that is relatively consistent across school environments, school context is crucial in connecting an individual's genotype to his or her likelihood of crossing meaningful educational thresholds.

Genetic nature or genetic nurture? Introducing social genetic parameters to quantify bias in polygenic score analyses.

Results from a genome-wide association study (GWAS) can be used to generate a polygenic score (PGS), an individual-level measure summarizing identified genetic influence on a trait dispersed across the genome. For complex, behavioral traits, the association between an individual's PGS and their phenotype may contain bias (from geographic, ancestral, and/or socioeconomic confounding) alongside the causal effect of the individual's genes. We formalize the introduction of a different source of bias in regression models using PGSs: the effects of parental genes on offspring outcomes, known as genetic nurture. GWAS do not discriminate between the various pathways through which genes become associated with outcomes, meaning existing PGSs capture both direct genetic effects and genetic nurture effects. We construct a theoretical model for genetic effects and show that the presence of genetic nurture biases PGS coefficients from both naïve OLS (between-family) and family fixed effects (within-family) regressions. This bias is in opposite directions; while naïve OLS estimates are biased away from zero, family fixed effects estimates are biased toward zero. We quantify this bias using two novel parameters: (1) the genetic correlation between the direct and nurture effects and (2) the ratio of the SNP heritabilities for the direct and nurture effects.