Effects of a GWAS-Supported Schizophrenia Variant in the DRD2 Locus on Disease Risk, Anhedonia, and Prefrontal Cortical Thickness

Abstract

The study aimed to confirm the association of the schizophrenia genome-wide association study (GWAS) hit rs2514218 located near the DRD2 gene with the risk of the disease and to investigate the relationships between rs2514218 and schizophrenia-related clinical and neuroimaging phenotypes. Genotypes at the rs2514218 site were determined for 2148 schizophrenia spectrum patients and 1273 control subjects from the Russian population. In subsets of subjects, we assessed symptomatic dimensions using the Positive and Negative Syndrome Scale (n = 1651) and Temporal Experience of Pleasure Scale (n = 471). At the brain level, gray matter volumes in striatal structures and cortical thickness in the lateral prefrontal cortical regions were investigated (n = 97). Genotype frequencies did not differ between patients and controls. The allelic association analysis yielded a near-threshold p value (p = 0.054), the magnitude (OR = 0.90), and direction of the minor allele (T) effect being in accord with those in the schizophrenia GWAS. Also, patients homozygous for the risk allele C had more severe consummatory anhedonia and a thinner cortex than controls and patients carrying the T allele. The largest effect size of the genotype with diagnosis interaction was seen in the right pars opercularis area. The findings support the role of rs2514218 in schizophrenia risk and presentation and suggest rs2514218 has an influence on brain morphology and negative symptoms.

Keywords: Brain morphology; Consummatory pleasure; DRD2; Gene; Psychosis.