Amy Adkins

Candidate gene-environment interaction research: reflections and recommendations.

Studying how genetic predispositions come together with environmental factors to contribute to complex behavioral outcomes has great potential for advancing the understanding of the development of psychopathology. It represents a clear theoretical advance over studying these factors in isolation. However, research at the intersection of multiple fields creates many challenges. We review several reasons why the rapidly expanding candidate gene–environment interaction (cG×E) literature should be considered with a degree of caution. We discuss lessons learned about candidate gene main effects from the evolving genetics literature and how these inform the study of cG×E. We review the importance of the measurement of the gene and environment of interest in cG×E studies. We discuss statistical concerns with modeling cG×E that are frequently overlooked. Furthermore, we review other challenges that have likely contributed to the cG×E literature being difficult to interpret, including low power and publication bias. Many of these issues are similar to other concerns about research integrity (e.g., high false-positive rates) that have received increasing attention in the social sciences. We provide recommendations for rigorous research practices for cG×E studies that we believe will advance its potential to contribute more robustly to the understanding of complex behavioral phenotypes.

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.

Integrating mRNA and miRNA Weighted Gene Co-Expression Networks with eQTLs in the Nucleus Accumbens of Subjects with Alcohol Dependence

Alcohol consumption is known to lead to gene expression changes in the brain. After performing weighted gene co-expression network analyses (WGCNA) on genome-wide mRNA and microRNA (miRNA) expression in Nucleus Accumbens (NAc) of subjects with alcohol dependence (AD; N = 18) and of matched controls (N = 18), six mRNA and three miRNA modules significantly correlated with AD were identified (Bonferoni-adj. p≤ 0.05). Cell-type-specific transcriptome analyses revealed two of the mRNA modules to be enriched for neuronal specific marker genes and downregulated in AD, whereas the remaining four mRNA modules were enriched for astrocyte and microglial specific marker genes and upregulated in AD. Gene set enrichment analysis demonstrated that neuronal specific modules were enriched for genes involved in oxidative phosphorylation, mitochondrial dysfunction and MAPK signaling. Glial-specific modules were predominantly enriched for genes involved in processes related to immune functions, i.e. cytokine signaling (all adj. p≤ 0.05). In mRNA and miRNA modules, 461 and 25 candidate hub genes were identified, respectively. In contrast to the expected biological functions of miRNAs, correlation analyses between mRNA and miRNA hub genes revealed a higher number of positive than negative correlations (χ2 test p≤ 0.0001). Integration of hub gene expression with genome-wide genotypic data resulted in 591 mRNA cis-eQTLs and 62 miRNA cis-eQTLs. mRNA cis-eQTLs were significantly enriched for AD diagnosis and AD symptom counts (adj. p = 0.014 and p = 0.024, respectively) in AD GWAS signals in a large, independent genetic sample from the Collaborative Study on Genetics of Alcohol (COGA). In conclusion, our study identified putative gene network hubs coordinating mRNA and miRNA co-expression changes in the NAc of AD subjects, and our genetic (cis-eQTL) analysis provides novel insights into the etiological mechanisms of AD.

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.

Genome-wide association data suggest ABCB1 and immune-related gene sets may be involved in adult antisocial behavior

Adult antisocial behavior (AAB) is moderately heritable, relatively common and has adverse consequences for individuals and society. We examined the molecular genetic basis of AAB in 1379 participants from a case–control study in which the cases met criteria for alcohol dependence. We also examined whether genes of interest were expressed in human brain. AAB was measured using a count of the number of Antisocial Personality Disorder criteria endorsed under criterion A from the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV). Participants were genotyped on the Illumina Human 1M BeadChip. In total, all single-nucleotide polymorphisms (SNPs) accounted for 25% of the variance in AAB, although this estimate was not significant (P=0.09). Enrichment tests indicated that more significantly associated genes were over-represented in seven gene sets, and most were immune related. Our most highly associated SNP (rs4728702, P=5.77 × 10−7) was located in the protein-coding adenosine triphosphate-binding cassette, sub-family B (MDR/TAP), member 1 (ABCB1). In a gene-based test, ABCB1 was genome-wide significant (q=0.03). Expression analyses indicated that ABCB1 was robustly expressed in the brain. ABCB1 has been implicated in substance use, and in post hoc tests we found that variation in ABCB1 was associated with DSM-IV alcohol and cocaine dependence criterion counts. These results suggest that ABCB1 may confer risk across externalizing behaviors, and are consistent with previous suggestions that immune pathways are associated with externalizing behaviors. The results should be tempered by the fact that we did not replicate the associations for ABCB1 or the gene sets in a less-affected independent sample.

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.

Genetic influences on adolescent behavior.

Adolescence is a transitional, developmental phase with marked shifts in behavior, particularly as related to risk-taking and experimentation. Genetic influences on adolescent behavior also show marked changes across this developmental period; in fact, adolescence showcases the dynamic nature of genetic influences on human behavior. Using the twin studies literature on alcohol use and misuse, we highlight several principles of genetic influence on adolescent behavior. We illustrate how genetic influences change (increase) across adolescence, as individuals have more freedom to express their predispositions and to shape their social worlds. We show how there are multiple genetic pathways to risk, and how the environment can moderate the importance of genetic predispositions. Finally, we review the literature aimed at identifying specific genes involved in adolescent behavior and understanding how identified genes impact adolescent outcomes. Ultimately, understanding how genetic predispositions combine with environmental influences to impact pathways of risk and resilience should be translated into improved prevention and intervention efforts; this remains a rich area for future research.

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.

Potentially Traumatic Events, Personality, and Risky Sexual Behavior in Undergraduate College Students.

Objective: Impulsivity and extraversion have demonstrated associations with risky sexual behavior (RSB) and potentially traumatic events (PTEs). In addition, interpersonal trauma appears to be associated with RSB, but research on the relationship between RSB and noninterpersonal PTEs (e.g., accidental) is lacking. The current study aims to investigate the relationships between personality (i.e., impulsivity, extraversion), RSB and multiple types of PTEs (i.e., accidental, physical, or sexual). Method: Personality and demographic characteristics were assessed during participants’ (N = 970) first semester of college, past-12 month PTEs and RSB were assessed during the second semester of participants’ junior year. Multiple linear regression was used to examine the relationship between PTEs, personality factors, and RSB. Analyses were also conducted to examine the potential mediating effect of interpersonal PTEs on the relationship between personality and RSB. Results: Impulsivity and extraversion were significantly positively associated with RSB. Both physical and sexual PTEs, but not accidental PTEs, were also significantly positively associated with RSB. Sexual PTEs significantly mediated the relationship between impulsivity and RSB. Conclusions: This is the first study to date to simultaneously examine the relationship between personality, RSB, and types of PTEs in a large sample of young adults. Exposure to interpersonal trauma appears to be a salient factor in the relationship between personality, specifically impulsivity, and RSB. These results indicate that college students may benefit from education regarding the potential negative outcomes of RSB, and that individuals with a history of interpersonal PTEs may be at increased risk for sexual risk taking.

Alcohol Use and Sexual and Physical Assault Victimization Among University Students: Three Years of Follow-Up:

The aim of this study was to determine the incidence of sexual and physical assault among university students and its association with alcohol use. The research is part of a wider cohort study (Spit for ScienceTM) at a large public university in the United States. The follow-up data include the first two cohorts (2011, 2012; n = 5,170). The dependent variables were victim of sexual assault and victim of physical assault. The independent variables were alcohol dependence and abuse according to the Diagnostic and Statistical Manual of Mental Disorders (4th ed.), cannabis use, residence, ethnicity, sexual orientation, and previous experience of sexual assault and/or physical assault. We used multilevel logistic regression for repeated measures. All data were analyzed using generalized linear mixed models. Incidence rates of sexual and physical assault (per 100 students a year) were 15.1 and 27.6 among nonabusers/dependents versus 36.4 and 56.7 among alcohol-dependent females at the first year, and 2.8 and 4.7 versus 7.7 and 23.1 at the third year; while in males, incident rates were 6.0 and 3.1 versus 18.5 and 66.6, and 2.3 and 7.4 versus 18.9 and 15.1, respectively. Our results show that alcohol abuse and dependence constitute risk factors to be victim of sexual assault in males (odds ratio [OR] = 2.21 and OR = 2.73) and alcohol dependence in females (OR = 2.16). Similarly, alcohol abuse and dependence are risk factors to physical assault among both males (OR = 1.52 and OR = 2.03) and females (OR = 1.70 and OR = 2.88). Ethnicity, sexual orientation, and whether the individual had been victimized in the past were associated with sexual assault. Regarding physical assault, cannabis use and past victimization are also risk factors. Our study has shown that assault victimization is strongly related to alcohol abuse and dependence diagnoses in both genders. Ethnicity and sexual orientation are also associated to both assaults. Our results show that incidence rates of both types of assaults were clearly higher in the first 6 months of university, probably explained by the novel and potentially risky environment.