Seung Bin Cho

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.

Genetic influences on alcohol use across stages of development: GABRA2 and longitudinal trajectories of drunkenness from adolescence to young adulthood

Longitudinal analyses allow us to understand how genetic risk unfolds across development, in a way that is not possible with cross‐sectional analyses of individuals at different ages. This has received little attention in genetic association analyses. In this study, we test for genetic effects of GABRA2, a gene previously associated with alcohol dependence, on trajectories of drunkenness from age 14 to 25. We use data from 1070 individuals who participated in the prospective sample of the Collaborative Study on the Genetics of Alcoholism, in order to better understand the unfolding of genetic risk across development. Piecewise linear growth models were fit to model the influence of genotype on rate of increase in drunkenness from early adolescence to young adulthood (14–18 years), the change in drunkenness during the transition to adulthood (18–19 years) and the rate of change in drunkenness across young adulthood (≥ 19 years). Variation in GABRA2 was associated with an increase in drunkenness that occurred at the transition between adolescence and adulthood. The genotypic effect was more pronounced in females. These analyses illustrate the importance of longitudinal data to characterize how genetic effects unfold across development. The findings suggest that transitions across important developmental periods may alter the relative importance of genetic effects on patterns of alcohol use. The findings also suggest the importance of considering gender when evaluating genetic effects on drinking patterns in males and females.

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.

Childhood Internalizing Symptoms Are Negatively Associated with Early Adolescent Alcohol Use

BACKGROUND The relationship between childhood internalizing problems and early adolescent alcohol use has been infrequently explored and remains unclear. METHODS We employed growth mixture modeling of internalizing symptoms for a large, population-based sample of U.K. children (the Avon Longitudinal Study of Parents and Children Cohort) to identify trajectories of childhood internalizing symptoms from age 4 through age 11.5. We then examined the relationship between membership in each trajectory and alcohol use in early adolescence (reported at age 13.8). RESULTS Overall, children experiencing elevated levels of internalizing symptoms were less likely to use alcohol in early adolescence. This finding held true across all internalizing trajectories; that is, those exhibiting increasing levels of internalizing symptoms over time, and those whose symptoms desisted over time, were both less likely to use alcohol than their peers who did not exhibit internalizing problems. CONCLUSIONS We conclude that childhood internalizing symptoms, unlike adolescent symptoms, are negatively associated with early adolescent alcohol experimentation. Additional studies are warranted to follow up on our preliminary evidence that symptoms of phobia and separation anxiety drive this effect.

The predictive power of family history measures of alcohol and drug problems and internalizing disorders in a college population

A family history (FH) of psychiatric and substance use problems is a potent risk factor for common internalizing and externalizing disorders. In a large web‐based assessment of mental health in college students, we developed a brief set of screening questions for a FH of alcohol problems (AP), drug problems (DP) and depression‐anxiety in four classes of relatives (father, mother, aunts/uncles/grandparents, and siblings) as reported by the student. Positive reports of a history of AP, DP, and depression‐anxiety were substantially correlated within relatives. These FH measures predicted in the student, in an expected pattern, dimensions of personality and impulsivity, alcohol consumption and problems, smoking and nicotine dependence, use of illicit drugs, and symptoms of depression and anxiety. Using the mean score from the four classes of relatives was more predictive than using a familial/sporadic dichotomy. Interactions were seen between the FH of AP, DP, and depression‐anxiety and peer deviance in predicting symptoms of alcohol and tobacco dependence. As the students aged, the FH of AP became a stronger predictor of alcohol problems. While we cannot directly assess the validity of these FH reports, the pattern of findings suggest that our brief screening items were able to assess, with some accuracy, the FH of substance misuse and internalizing psychiatric disorders in relatives. If correct, these measures can play an important role in the creation of developmental etiologic models for substance and internalizing psychiatric disorders which constitute one of the central goals of the overall project.

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.

Longitudinal investigation of interpersonal trauma exposure and alcohol use trajectories

BACKGROUND The current longitudinal study examined associations between interpersonal potentially traumatic events (PTEs; i.e., sexual or physical assault) and changes in alcohol consumption among incoming college students. METHODS 1197 students (68% female) participating in a university-wide research study were included in analyses. Assessments were administered at three time-points and included measures of alcohol use, PTEs (Life Events Checklist), and a screener for possible PTSD symptoms (abbreviated Primary Care PTSD Screen). Linear growth curve models were fit to the three repeated measures of alcohol quantity and frequency to determine the role of pre-college and college-onset interpersonal PTEs and possible PTSD symptoms on patterns of alcohol use. RESULTS Pre-college interpersonal PTE was associated with greater baseline alcohol use for female but not male students. College-onset interpersonal PTE predicted greater alcohol use at concurrent and future assessments for women but not men, beyond the effects of pre-college PTE. Pre-college possible PTSD symptoms did not predict baseline or change in alcohol use. CONCLUSIONS There may be a stronger and longer-lasting impact of interpersonal PTE for college women compared to men on alcohol phenotypes, although replication in studies oversampling men endorsing interpersonal PTE is needed.

Gender and Direction of Effect of Alcohol Problems and Internalizing Symptoms in a Longitudinal Sample of College Students

ABSTRACT Background: Alcohol problems and internalizing symptoms are consistently found to be associated but how they relate to each other is unclear. Objective: The present study aimed to address limitations in the literature of comorbidity of alcohol problems and internalizing symptoms by investigating the direction of effect between the phenotypes and possible gender differences in college students. Method: We utilized data from a large longitudinal study of college students from the United States (N = 2607). Three waves of questionnaire-based data were collected over the first two years of college (in 2011–2013). Cross-lagged models were applied to examine the possible direction of effect of internalizing symptoms and alcohol problems. Possible effects of gender were investigated using multigroup modeling. Results: There were significant correlations between alcohol problems and internalizing symptoms. A direction of effect was found between alcohol problems and internalizing symptoms but differed between genders. A unidirectional relationship varying with age was identified for males where alcohol problems initially predicted internalizing symptoms followed by internalizing symptoms predicting alcohol problems. For females, a unidirectional relationship existed wherein alcohol problems predicted internalizing symptoms. Conclusions/Importance: We conclude that the relationship between alcohol problems and internalizing symptoms is complex and differ between genders. In males, both phenotypes are predictive of each other, while in females the relationship is driven by alcohol problems. Importantly, our study examines a population-based sample, revealing that the observed relationships between alcohol problems and internalizing symptoms are not limited to individuals with clinically diagnosed mental health or substance use problems.

Studies Of Alcohol Related Phenotypes Across Human, Mouse And Invertebrate Models

Background Genetic influences on alcohol dependence (AD) have been well established, with the heritability of AD as estimated in behavioral genetic studies ranging from 50-60%. However, robust genetic association signals in human studies of AD have been limited. As part of the VCU Alcohol Research Center, we use multiple model organism systems (C. Elegans, Drosophila, mouse, and rat) and human studies to advance our understanding of the genetic basis of alcohol related outcomes. Molecular responses to ethanol are likely to be shared across species because signaling mechanisms are evolutionarily conserved. As individual genes and gene networks are associated with ethanol response in model organisms, it is critical to understand their association with human alcohol related phenotypes. In this study we tested the effect of several gene sets identified through model organism research with a range of phenotypes hypothesized to be involved in alcohol-related outcomes in human studies. Methods All the sets and genes were tested using one of the two related software depending if the sample contains independent individuals (Plink set based analysis) or the sample has dependent individuals (Gskat). In all human samples we used imputed data if available. Plink uses algorithm based on significant pruned SNPs (r^2=0.5) at the threshold (p=0.05) keeping LD structure and permuting phenotype randomly between individuals. Gskat performs Family based association test for sets via GEE Kernel Machine score test. We used covariates same as in previous GWAS and other analyses for each of the samples. Results We find evidence that there is some evidence of association in human samples in all three considered gene sets and genes separately for some considered phenotypes. Max number of drinks was strongly associated with several genes in human samples. Externalizing phenotype also showed association with several genes across most human samples. Considering several human samples allows us more preciously determine gene structure affecting alcohol related phenotypes. Discussion In these analyses we tested gene sets with known association in mouse and invertebrate models for the association in human samples using alcohol related phenotypes in an effort to characterize similarities between human phenotypes and animal analogues. It is important to take into account the multiple pathways by which genes may exert an effect on alcohol problems in humans. Analogues between human and animal models will help with explaining the biological and functional reasons creating behavioral problems.