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S081-2

Gabaergic Genetic Investigations into Impaired Inhibitory Control in Cocaine
Dependence

Bao-Zhu Yang

Yale University, USA

Background/Objective: GABA is one of the most common and potent inhibitory neurotransmitters
in human brain. Clinically impaired inhibition control in cocaine dependence (CD) individuals have
been evident. This deficit could be due to an interaction between pre-existing genetic susceptibilities
in GABA-related genes with effects of cocaine use on the brain; however, this interaction mechanism
is not understood. We aimed to investigate the genetic and neurobiological underpinnings of
impaired inhibition in CD individuals for African American (AA) through examining neural
activation of whole brain and related brain circuitries via functional magnetic resonance image
(fMRI) using a STROOP task, and genome-wide and exome-wide array-based genotyping
technologies. The 67 fMRI scanned subjects were genotyped using the Exome-array and imputed
using 1000 genome as reference. We identified 43 unique genes in the GABAergic pathways and a
total of 3,309 SNPs passed the quality control and pruning for further analysis. We used a large-scale
substance dependence cohort of 3,318 AA subjects to generate reference relative risk in CD for the
fMRI scanned subjects of CD and matched unrelated healthy controls (HC). The GABAergic genetic
risk scores for CD and HC is significantly different (p=0.013). The blood oxygen level dependent
(BOLD) signal changes for the STROOP contrast of incongruent versus congruent identified two
clusters correlated with the polygenic risk scores of CD for a smaller sample of eleven CD subjects:
one cluster in left precentral gyrus and another in left precunesus, both of which have been
implicated in cognitive inhibition and attention network, respectively. The analysis for this study is
still on-going.

Conclusion: In conclusion, the observed differences in neural responses to inhibition control in
correlation with the GABAergic genes suggest that individual differences in genetic composition
linked to GABAergic function contribute significantly to inhibition control processes and warrant
further investigation in treatment development for CD.