Contrasting changes in DRD1 and DRD2 splice variant expression in schizophrenia and affective disorders, and associations with SNPs in postmortem brain

Dopamine 2 receptor (DRD2) is of major interest to the pathophysiology of schizophrenia (SCZ) both as a target for antipsychotic drug action as well as a SCZ-associated risk gene. The dopamine 1 receptor (DRD1) is thought to mediate some of the cognitive deficits in SCZ, including impairment of working memory that relies on normal dorsolateral prefrontal cortex (DLPFC) function. To better understand the association of dopamine receptors with SCZ, we studied the expression of three DRD2 splice variants and the DRD1 transcript in DLPFC, hippocampus and caudate nucleus in a large cohort of subjects (similar to 700), including patients with SCZ, affective disorders and nonpsychiatric controls (from 14th gestational week to 85 years of age), and examined genotype-expression associations of 278 single-nucleotide polymorphisms (SNPs) located in or near DRD2 and DRD1 genes. Expression of D2S mRNA and D2S/D2-long (D2L) ratio were significantly increased in DLPFC of patients with SCZ relative to controls (P < 0.0001 and P < 0.0001, respectively), whereas D2L, D2Longer and DRD1 were decreased (P < 0.0001). Patients with affective disorders showed an opposite pattern: reduced expression of D2S (major depressive disorder, P < 0.0001) and increased expression of D2L and DRD1 (bipolar disorder, P < 0.0001). Moreover, SCZ-associated risk alleles at rs1079727, rs1076560 and rs2283265 predicted increased D2S/D2L expression ratio (P < 0.05) in control individuals. Our data suggest that altered splicing of DRD2 and expression of DRD1 may constitute a pathophysiological mechanism in risk for SCZ and affective disorders. The association between SCZ risk-associated polymorphism and the ratio of D2S/D2L is consistent with this possibility.