Megan E. Cooke

Spit for Science: launching a longitudinal study of genetic and environmental influences on substance use and emotional health at a large US university.

Finding genes involved in complex behavioral outcomes, and understanding the pathways by which they confer risk, is a challenging task, necessitating large samples that are phenotypically well characterized across time. We describe an effort to create a university-wide research project aimed at understanding how genes and environments impact alcohol use and related substance use and mental health outcomes across time in college students. Nearly 70% of the incoming freshman class (N = 2715) completed on-line surveys, with 80% of the students from the fall completing spring follow-ups. 98% of eligible participants also gave DNA. The participants closely approximated the university population in terms of gender and racial/ethnic composition. Here we provide initial results on alcohol use outcomes from the first wave of the sample, as well as associated predictor variables. We discuss the potential for this kind of research to advance our understanding of genetic and environment influences on substance use and mental health outcomes.

Patterns of Substance Use Across the First Year of College and Associated Risk Factors.

Starting college is a major life transition. This study aims to characterize patterns of substance use across a variety of substances across the first year of college and identify associated factors. We used data from the first cohort (N = 2056, 1240 females) of the “Spit for Science” sample, a study of incoming freshmen at a large urban university. Latent transition analysis was applied to alcohol, tobacco, cannabis, and other illicit drug uses measured at the beginning of the fall semester and midway through the spring semester. Covariates across multiple domains – including personality, drinking motivations and expectancy, high school delinquency, peer deviance, stressful events, and symptoms of depression and anxiety – were included to predict the patterns of substance use and transitions between patterns across the first year. At both the fall and spring semesters, we identified three subgroups of participants with patterns of substance use characterized as: (1) use of all four substances; (2) alcohol, tobacco, and cannabis use; and (3) overall low substance use. Patterns of substance use were highly stable across the first year of college: most students maintained their class membership from fall to spring, with just 7% of participants in the initial low substance users transitioning to spring alcohol, tobacco, and cannabis users. Most of the included covariates were predictive of the initial pattern of use, but covariates related to experiences across the first year of college were more predictive of the transition from the low to alcohol, tobacco, and cannabis user groups. Our results suggest that while there is an overall increase in alcohol use across all students, college students largely maintain their patterns of substance use across the first year. Risk factors experienced during the first year may be effective targets for preventing increases in substance use.

Molecular Genetic Influences on Normative and Problematic Alcohol Use in a Population-Based Sample of College Students

Background: Genetic factors impact alcohol use behaviors and these factors may become increasingly evident during emerging adulthood. Examination of the effects of individual variants as well as aggregate genetic variation can clarify mechanisms underlying risk. Methods: We conducted genome-wide association studies (GWAS) in an ethnically diverse sample of college students for three quantitative outcomes including typical monthly alcohol consumption, alcohol problems, and maximum number of drinks in 24 h. Heritability based on common genetic variants (h2SNP) was assessed. We also evaluated whether risk variants in aggregate were associated with alcohol use outcomes in an independent sample of young adults. Results: Two genome-wide significant markers were observed: rs11201929 in GRID1 for maximum drinks in 24 h, with supportive evidence across all ancestry groups; and rs73317305 in SAMD12 (alcohol problems), tested only in the African ancestry group. The h2SNP estimate was 0.19 (SE = 0.11) for consumption, and was non-significant for other outcomes. Genome-wide polygenic scores were significantly associated with alcohol outcomes in an independent sample. Conclusions: These results robustly identify genetic risk for alcohol use outcomes at the variant level and in aggregate. We confirm prior evidence that genetic variation in GRID1 impacts alcohol use, and identify novel loci of interest for multiple alcohol outcomes in emerging adults. These findings indicate that genetic variation influencing normative and problematic alcohol use is, to some extent, convergent across ancestry groups. Studying college populations represents a promising avenue by which to obtain large, diverse samples for gene identification.

Post-GWAS in Psychiatric Genetics: A Developmental Perspective on the “Other” Next Steps

As psychiatric genetics enters an era where gene identification is finally yielding robust, replicable genetic associations and polygenic risk scores, it is important to consider next steps and delineate how that knowledge will be applied to ultimately ameliorate suffering associated with substance use and psychiatric disorders. Much of the post‐genome‐wide association study discussion has focused on the potential of genetic information to elucidate the underlying biology and use this information for the development of more effective pharmaceutical treatments. In this review we focus on additional areas of research that should follow gene identification. By taking genetic findings into longitudinal, developmental studies, we can map the pathways by which genetic risk manifests across development, elucidating the early behavioral manifestations of risk, and studying how various environments and interventions moderate that risk across developmental stages. The delineation of risk across development will advance our understanding of mechanism, sex differences and risk and resilience processes in different racial/ethnic groups. Here, we review how the extant twin study literature can be used to guide these efforts. Together, these new lines of research will enable us to develop more informed, tailored prevention and intervention efforts.

The utility of a brief web-based prevention intervention as a universal approach for risky alcohol use in college students : Evidence of moderation by family history

Background: Alcohol use on college campuses is prevalent and contributes to problems that affect the health, emotional wellbeing, and academic success of college students. Risk factors, such as family history of alcohol problems, predict future alcohol problems, but less is known about their potential impact on intervention effectiveness. The purpose of this study was to examine the effect of an intervention implemented in a non-randomized sample of drinking and non-drinking college freshmen. Methods: Freshmen college students recruited for the intervention study (n = 153) completed a web-adaptation of the Brief Alcohol Screening and Intervention for College Students (BASICS) at the start of spring semester. We compared their 30-days post-intervention alcohol initiation, number of drinking days (DAYS), drinks per occasion (DRINKS), maximum drinks in 24 h (MAX24) and alcohol use disorder symptoms (AUDsx) to 151 comparison participants retrospectively matched on demographics and baseline alcohol use behaviors. We also tested baseline DRINKS, DAYS, AUDsx, MAX24, and parental family history (PFH) of alcohol problems as moderators of the effect of the intervention. Results: At follow-up, intervention participants had lower rates of AUDsx than comparison participants, especially among baseline drinkers. Among participants drinking 3+ days/month at baseline, intervention participants showed fewer DAYS at follow-up than the comparison group participants. BASICS was also associated with a decreased likelihood of initiation among baseline non-drinkers. PFH significantly interacted with treatment group, with positive PFH intervention participants reporting significantly fewer AUDsx at follow-up compared to positive PFH comparison participants. We found no evidence for an effect of the intervention on DRINKS or MAX24 in our analyses. Conclusions: Results suggest some indication that novel groups, such as non-drinkers, regular drinkers, and PFH positive students may experience benefits from BASICS. Although conclusions were limited by lack of randomization and short follow-up period, PFH positive and low to moderate drinking groups represent viable targets for future randomized studies.

Alcohol Misuse Across the Life Span: Insights From Developmental Studies in Behavior Genetics

Alcohol misuse, one of today’s greatest public health challenges, is a developmentally dynamic, complex behavior at the intersection of genetic and environmental influences. This review examines such influences from a behavior genetics perspective and discusses implications for public policy. Alcohol misuse is moderately heritable with genetic influences accounting for around 50% of its variance, but to date, few specific genes have been identified. However, numerous environmental and social factors moderate genetic risk, including parents, peers, romantic partners, family dynamics, employment, laws, and cultural influences. These moderating factors change in salience across development, and accordingly, no one-size-fits-all approach is suitable for reducing alcohol misuse at a large scale. We provide examples of some effective prevention and intervention programs and discuss a framework for using the behavior genetics evidence to inform future public policy efforts.

Genome-Wide Polygenic Atlas of the Phenome in Emerging Adulthood: Prediction of Behavioral and Health Outcomes

Background Identifying genetic relationships between complex traits in emerging adulthood can provide useful etiological insights into risk for psychopathology and other adverse outcomes. This study examined genomic data from a large sample of emerging adults (N = 5,947) to construct an atlas of polygenic risk that indexes diverse psychiatric, behavioral and health outcomes. Methods Genome-wide association studies of 34 diverse psychiatric phenotypes and health factors were used as discovery samples to calculate genome-wide polygenic scores (GPS), which were then used to predict 55 phenotypes in the emerging adults. Special emphasis was placed on replicating previously published phenotypic and genetic relationships. All analyses were tested separately in each ancestry group (based on 1000 Genomes super-populations) and corrected for multiple testing within group. Results The analyses resulted in over 1,800 associations between GPS and phenotype, with over 80 reaching significance. The majority of previously published hypotheses were replicated. A number of notable findings emerged beyond the expected within-trait prediction (GPS for height and body mass index predicted phenotypic height and BMI, respectively). The GPS for schizophrenia predicted depressive symptoms, anxiety symptoms, and nicotine use, as well as experiences of interpersonal trauma and family history of mental health problems. The neuroticism GPS significantly predicted general anxiety, phobia, insomnia, phenotypic neuroticism, and depressive symptoms. Conversely, the subjective well-being GPS predicted fewer depressive symptoms, fewer anxiety symptoms, decreased family history of mental health problems, as well as increased social support and relationship satisfaction. Many of these associations were consistent across ancestry groups. Discussion These results highlight the utility of a comprehensive polygenic modeling framework, and provide potential avenues for prediction of risk and resilience in emerging adulthood. While the variance explained by any of these GPSs is small, they provide easily accessible information to guide future prediction, prevention, and intervention efforts to improve health and quality of life outcomes. Furthermore, many distinct GPS displayed significant prediction of the same phenotypes, indicating that more cross-trait research is needed to better understand the complex pattern of relationships between psychiatric outcomes.

Genome-Wide Polygenic Atlas of The Phenome In Emerging Adulthood: Genetic Overlap of Risk Across Five Ancestries

Background Creating a network of the genetic relationships between multiple psychiatric and medical traits, during a critical developmental period, can enhance our understanding of risk for psychopathology. This study utilized genomic data from emerging adults (N = 5,947) to construct a comprehensive atlas of polygenic risk that indexes diverse psychiatric, behavioral and health outcomes. Methods In addition to testing the GPSs prediction of the phenotypes (Moscati & Docherty, et al., this meeting), GPSs were also examined for associations with each other in this sample, across five ethnicities..Genome-wide association studies of 34 diverse phenotypes were used as as discovery samples to calculate genome-wide polygenic scores (GPS), and these scores were then used to predict over 50 phenotypes in the emerging adults. We computed partial correlations adjusted for ancestry principle components in order to estimate genetic relationships between the phenotypes, and corrected for multiple testing. Based on the cross-disorder psychiatric genomics findings to date, we hypothesized significant GPS associations between five major psychiatric disorders across each of the ancestry groups. We also attempted to replicate the associations reported in a previously derived atlas by Bulik-Sullivan and colleagues. Results Several significant associations were observed in the European sample: SZ~BP (β = 0.73, p = 2.7*10-67), BP~MDD (β = 0.23, p = 4.6*10-33), and SZ~MDD (β = 0.43, p = 7.2*10-21). Significant associations were not observed for AUT~ADHD (β =-0.005, p = 0.04) or AUT~SZ (β = 0.005, p = 0.19). All of the GPS regression replications from the previous atlas were robustly significant and all were consistent with the sign of the previously published coefficients. Importantly, some unexpected but informative associations were observed: for example, significant positive associations of neuroticism GPS with GPSs for triglycerides and for coronary artery disease. We also present these regressions across the four additional ancestry groups, with a majority of the significant associations holding in these groups. Discussion The findings here present a wide-ranging and nuanced picture of major dimensions of vulnerability to psychopathology at a genetic level. Overall, results reflect relationships between anxiety, depressive, and schizophrenia-spectrum disorders that are largely consistent with our current conceptualizations of diagnostic classification and confirm the important involvement of a network of medical and risk phenotypes in genetic predisposition to these disorders. Findings relating genetic risk for neuroticism with genetic risk for cardiovascular phenotypes may have important implications for psychiatry and public health.