GABRA2 rs279858-linked variants are associated with disrupted structural connectome of reward circuits in heroin abusers

The reward system plays a vital role in drug addiction. The purpose of this study is to investigate the structural connectivity characteristics and driving-control subnetwork patterns of reward circuits in heroin abusers and assess the genetic modulation on the reward network. We first defined the reward network based on systematic literature review, and built the reward network based on diffusion tensor imaging data of 78 heroin abusers (HAs) and 79 healthy controls (HCs) using structural connectomics. Then we assessed genetic factors that might modulate changes in the reward network by performing imaging-genetic screening for 22 addiction-related polymorphisms. The genetic association was validated by performing genetic associations (1032 HAs and 2863 HCs) and expanded-variant analysis. Finally, we estimated the association between these genetic variations, reward network, and clinical performance. We found that HAs had widespread deficiencies in the structural connectivity of the reward circuit (center in VTA-linked connections), which correlated with cognition deficiency. The disruptions synchronously were shown on the reward driving system and reward control system. GABRA2 rs279858-linked variants might be a key genetic modulator for heroin vulnerability by affecting the connections of reward network and cognition. The role of the reward network connections that mediates the effects of rs279858 on cognition would be disrupted by heroin addiction. These findings provide new insights into the neurocircuitry and genetic mechanisms of addiction.