Effects of common and rare GABAergic gene variation on alcohol use and antisocial behavior

Abstract

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Epidemiological estimates suggest that nearly half of individuals diagnosed with AUD will also be diagnosed with another mental health disorder, with some of the strongest associations involving AUD and other externalizing disorders. Previous studies investigating the relation between AUD and externalizing behaviors with a cluster of [gamma]- aminobutyric acid (GABA) receptor genes (GABRG1-A2-A4-B1) located on chromosome 4 have generated varying results. The current study is an effort to examine the effects of common and rare variation in this GABAergic gene cluster in relation to externalizing behavior utilizing genetic sequencing data. A subset of the UCSF Family Alcoholism Sample (N=1610) was used to conduct common and rare variant association analyses of this GABAergic cluster with DSM-5 AUD symptom counts, antisocial personality (ASP) , and an AUD/ASP interaction term representing a broader externalizing phenotype. The single-variant tests of ASP yielded the strongest association with rs11941860 located in GABRG1, and the top associations for AUD (rs3756007) and the interaction term (rs2119183) were both located in the GABRA2 region. For the gene-based analyses, the only association that was found was between rare variants in GABRA2 and the interaction term. Common and rare variant associations for the interaction persisted when covarying for the effects of the other type of variation, suggesting that unique common and rare variant associations in GABRA2 confer risk for AUD and antisocial behaviors, which may indicate liability towards a broader externalizing phenotype.