Role of GABRA2 in Trajectories of Externalizing Behavior Across Development and Evidence of Moderation by Parental Monitoring

Abstract

Context As we identify genes involved in psychiatric disorders, the next step will be to study how the risk associated with susceptibility genes manifests across development and in conjunction with the environment. We describe analyses aimed at characterizing the pathway of risk associated with GABRA2, a gene previously associated with adult alcohol dependence, in a community sample of children followed longitudinally from childhood through young adulthood. Objective To test for an association between GABRA2 and trajectories of externalizing behavior from adolescence to young adulthood and for moderation of genetic effects by parental monitoring. Design Data were analyzed from the Child Development Project, with yearly assessments conducted since that time. A saliva sample was collected for DNA at the 2006 follow-up, with a 93% response rate in the target sample. Growth mixture modeling was conducted using Mplus to identify trajectories of externalizing behavior and to test for effects of GABRA2 sequence variants and parental monitoring. Setting Nashville and Knoxville, Tennessee, and Bloomington, Indiana. Participants A community-based sample of families enrolled at 3 sites as children entered kindergarten in 1987 and 1988. Analyses for the white subset of the sample (n=378) are reported here. Main Outcome Measures Parental monitoring measured at 11 years of age; Child Behavior Checklist youth reports of externalizing behavior at ages 12, 14, 15, 16, 17, 19, 20, 21, and 22 years. Results Two classes of externalizing behavior emerged: a stable high externalizing class and a moderate decreasing externalizing behavior class. The GABRA2 gene was associated with class membership, with subjects who showed persistent elevated trajectories of externalizing behavior more likely to carry the genotype previously associated with increased risk of adult alcohol dependence. A significant interaction with parental monitoring emerged; the association of GABRA2 with externalizing trajectories diminished with high levels of parental monitoring. Conclusions These analyses underscore the importance of studying genetic effects across development and of identifying environmental factors that moderate risk.

Effect of GABRA2 Genotype on Development of Incentive-Motivation Circuitry in a Sample Enriched for Alcoholism Risk

“…The G allele of GABRA2 SNP rs279858 has been associated with adult alcohol dependence (Covault et al, 2004), elevated externalizing problems throughout adolescence (Dick et al, 2009), impulsiveness (Villafuerte et al, 2012), and increased insula activation during incentive anticipation (Villafuerte et al, 2012). We show that activation of the NAcc to incentive stimuli is heightened in G carriers during adolescence.…”

“…The less frequent haplotype has been associated with alcoholics without comorbid drug dependence (Covault et al, 2004) and those with a family history of alcoholism (Fehr et al, 2006). This haplotype is also associated with childhood and adolescent phenotypic precursors to alcohol dependence, including externalizing problems throughout adolescence (Dick et al, 2009) and impulsiveness (Villafuerte et al, 2012).…”

“…The present report is based on 473 scans covering ages 8-27 years. We investigated SNP rs279858; the minor (G) allele, a tag allele for the less frequent GABRA2 haplotype, has been associated with adult alcohol dependence (Covault et al, 2004) as well as adolescent externalizing problems (Dick et al, 2009) and impulsiveness (Villafuerte et al, 2012). Based on evidence of a positive relationship between NAcc activation to anticipation of reward during the MID and externalizing problems , impulsivity (Hahn et al, 2009) and sensation-seeking (Bjork et al, 2008a), we hypothesized that G allele carriers would have heightened NAcc response.…”

Conclusions: Consilience as the Future of Addiction Psychopharmacology

“…The cognitive neuroscience methodologies, especially, offer powerful tools to examine the phenotypic expression of genotypic variation in brain activity (e.g., Edenberg et al, 2004;Filbey et al, 2008;McClernon, Hutchison, Rose, and Kozink, 2007; for a review, see Green et al, 2008). However, there is also promise for many of the other experimental domains reviewed, such as subjective intoxication (e.g., Dlugos et al, 2010;Ray and Hutchison, 2004), cue reactivity (Hutchison et al, 2002;van den Wildenberg et al, 2007), aspects of impulsivity (e.g., Eisenberg et al, 2007;Hamidovic et al, 2009), and even developmental trajectories (e.g., Dick et al, 2009). Although it is highly likely that each of these phenotypes in themselves will be complex, with variation reflecting the influences of tens, hundreds, or even thousands of loci, they may nonetheless be important mechanistic processes that add to our understanding of latent vulnerabilities to addiction.…”

Parental Monitoring Sources, Ethnicity, and Child Problem Behaviors

“…A limited number of studies have examined the specific sources of parental monitoring as they relate to child behavioral outcomes (Dishion, et al, 1991;Dick et al, 2009& Fulkerson, Pasch, Perry, & Komro, 2008. In the literature on the relationship between monitoring and child outcomes, only three studies were identified that utilized the specific sources of parental monitoring (Crouter, et.…”