Effects of Trans-ancestry Schizophrenia Risk Gene Polymorphisms on Working Memory and Underlying Brain Mechanisms

One of the main goals of the new generation of antipsychotics is to improve cognitive functions of schizophrenia patients, which makes it necessary to identify genes related to not only schizophrenia but also its cognitive impairments. Starting with 58 trans-ancestry risk variants found in a genome-wide association study of Chinese schizophrenia patients, we conducted two studies with four samples to systematically examine these variants' potential roles in working memory. Study 1 was a behavioral study (Sample I included 510 healthy volunteers who completed the n-back, dot-pattern expectancy [DPX], delayed match-to-sample [DMS], and spatial span tasks; Sample II included 819 healthy volunteers and 893 schizophrenia patients who completed the n-back and DPX tasks). Study 2 was an fMRI study (Sample III included 163 healthy volunteers and 52 schizophrenia patients, who were scanned with fMRI during an n-back task; and Sample IV included 89 healthy volunteers, who were scanned during a spatial span task). Sample I identified rs11210892 as the only SNP that was associated with performance on multiple tasks (n-back, DPX, and DMS) after Bonferroni correction. Sample II replicated this association on the n-back task and the DPX task. FMRI data showed that the risk allele "G" of rs11210892 was associated with an increased activation within the right dorsolateral prefrontal cortex (Sample III) and the bilateral striatum (Sample IV). We conclude that rs11210892 is significantly associated with working memory and its neural underpinnings, so the genes near this SNP might be potential gene targets for treating cognitive impairment associated with schizophrenia.