Genetic and Neurobiological Influences on Internalizing Characteristics in Binge Drinkers

Previous research has hypothesized a developmental pathway to alcohol use disorder characterized by internalizing symptoms (Hussong et al., 2011; Psychol Addict Behav 25, 390-404). This pathway has been predominantly... [ view full abstract ]

Previous research has hypothesized a developmental pathway to alcohol use disorder characterized by internalizing symptoms (Hussong et al., 2011; Psychol Addict Behav 25, 390-404). This pathway has been predominantly researched and characterized in terms of self-reported phenotypic characteristics.  However, less work has been done to determine whether individuals in this pathway are distinct in their underlying biological processes.  The majority of gene finding studies treat alcohol misusers as a homogeneous group ignoring the possibility of potential genetic subtypes that correlate with the phenotypic subtypes described in the literature.  To help fill this gap, the current study uses 3,079 regular binge drinkers from an ethnically diverse university-wide longitudinal study (Dick et al., 2014; Front Genet 5:47) to explicitly examine internalizing characteristics in the context of heavy drinking.  Due to the ethnic diversity of the sample, analyses were conducted separately by ancestry, and then meta-analyzed (Webb et al., 2017; Front Genet 8:30).  Genome-wide association analyses showed five genome-wide significant markers in the RPH3AL gene (p< 5.0x10^-8, q<0.08).  An additional seven markers in this gene were marginally significant (p = 6.61x10^-8 – 2.38x10^-7, q = 0.08 – 0.14).  These markers were neither genome-wide significant nor marginally significant in genome-wide association analyses of internalizing characteristics in the full sample which includes individuals with lighter drinking patterns.  This suggests that this gene is uniquely associated with the combination of internalizing characteristics and heavy drinking reiterating the importance of incorporating phenotypic heterogeneity in genetic analyses.  A portion of this sample (current N=36) is undergoing a neuroimaging protocol.  Forthcoming analyses will examine associations between RPH3AL and relevant neuroimaging outcomes as well as the potential mediating role of brain activation in the association between RPH3AL and internalizing binge drinking.