GRM8 genotype is associated with externalizing disorders and greater inter-trial variability in brain activation during a response inhibition task

Objective The present investigation tested the association of a novel measure of brain activation recorded during a simple motor inhibition task with a GRM8 genetic locus implicated in risk for substance dependence. Methods 122 European-American adults were genotyped at rs1361995 and evaluated against DSM-IV criteria for Alcohol Dependence, Cocaine Dependence, Conduct Disorder, and Antisocial Personality Disorder. Also, their brain activity was recorded in response to rare, so-called “No-Go” stimuli presented during a continuous performance test. Brain activity was quantified with two indices: (1) the amplitude of the No-Go P300 electroencephalographic response averaged across trials; and (2) the inter-trial variability of the response. Results The absence of the minor allele at the candidate locus was associated with all of the evaluated diagnoses. In comparison to minor allele carriers, major allele homozygotes also demonstrated increased inter-trial variability in No-Go P300 response amplitude but no difference in average amplitude. Conclusions GRM8 genotype is associated with Alcohol and Cocaine Dependence as well as personality risk factors for dependence. The association may be mediated through an inherited instability in brain function that affects cognitive control. Significance The present study focuses on a metric and brain mechanism not typically considered or theorized in studies of patients with substance use disorders.