The genetic influence of the DRD3 rs6280 polymorphism (Ser9Gly) on functional connectivity and gray matter volume of the hippocampus in patients with first-episode, drug-naïve schizophrenia

Abstract

The D3 dopamine receptor (DRD3) plays a major role in cognitive function and is a candidate gene for schizophrenia. DRD3 is widely distributed in the hippocampus, but whether there are potential associations between the rs6280 genotype, the hippocampus, and cognitive function in first-episode, drug-naïve (FES) patients and healthy controls (HCs) is still poorly understood. First, using functional and structural magnetic resonance imaging data, we calculated the gray matter volume (GMV) and functional connectivity (FC) of the hippocampus. Then, we examined the possible interaction effect of the DRD3 genotype and the disease on the FC and GMV of the hippocampus in 52 FES patients and 51 HCs. Finally, the correlation between the FC and GMV in the hippocampus, influenced by rs6280, and the cognitive performance of subjects was analyzed. A significant interaction effect of diagnostic group by genotype of rs6280 on the GMV of the left hippocampus was found, with lower GMV in FES patients that were C carriers compared with TT homozygotes; the opposite pattern was found in the genetic subgroups of HCs. In the FES group, C carriers performed significantly worse on reasoning and problem-solving tests than TT homozygotes. The left hippocampal GMV positively correlated with reasoning and problem-solving performance in TT homozygotes, but this correlation disappeared in FES patients that were C carriers and in genetic subgroups of HCs. Together, these results suggest that FES patients that are C carriers of rs6280 have lower GMV in the hippocampus, resulting in greater cognitive impairment.