Functional variants of the dopamine receptor D2 gene modulate prefronto-striatal phenotypes in schizophrenia

Abstract

Dopamine D2 receptor signalling is strongly implicated in the aetiology of schizophrenia. We have recently characterized the function of three DRD2 SNPs: rs12364283 in the promoter affecting total D2 mRNA expression; rs2283265 and rs1076560, respectively in introns 5 and 6, shifting mRNA splicing to two functionally distinct isoforms, the short form of D2 (D2S) and the long form (D2L). These two isoforms differentially contribute to dopamine signalling in prefrontal cortex and in striatum. We performed a case-control study to determine association of these variants and of their main haplotypes with several schizophrenia-related phenotypes. We demonstrate that the minor allele in the intronic variants is associated with reduced expression of %D2S of total mRNA in post-mortem prefrontal cortex, and with impaired working memory behavioural performance, both in patients and controls. However, the fMRI results show opposite effects in patients compared with controls: enhanced engagement of prefronto-striatal pathways in controls and reduced activity in patients. Moreover, the promoter variant is also associated with working memory activity in prefrontal cortex and striatum of patients, and less robustly with negative symptoms scores. Main haplotypes formed by the three DRD2 variants showed significant associations with these phenotypes consistent with those of the individual SNPs. Our results indicate that the three functional DRD2 variants modulate schizophrenia phenotypes possibly by modifying D2S/D2L ratios in the context of different total D2 density.

Fig. 1

Mean ± 0.95 confidence intervals (CIs) of prefrontal %D2S mRNA in patients and controls; S = short.

Fig. 2

(A) 3D rendering (above, image thresholded at P < 0.005, uncorrected) and mean ± 0.95 CIs of BOLD response (below) of the interaction between diagnosis and rs1076560 genotype on WM prefrontal activity. (B) Coronal section (above) and mean ± 0.95 CIs of BOLD response (below) of the interaction between diagnosis and rs1076560 genotype on WM activity in the left head of the caudate.

Fig. 3

(A) Coronal section (image thresholded at P < 0.005, uncorrected) of the BOLD response of the interaction between diagnosis and rs12364283 genotype on WM activity in the striatum (above). Mean ± 0.95 CIs of the BOLD response in left putamen in patients and controls separated for rs12364283 genotype (below). (B) 3D rendering (image thresholded at P < 0.005, uncorrected) of BOLD response of the interaction between diagnosis and rs12364283 genotype on WM prefrontal activity (above). Mean ± 0.95 CIs of the BOLD response in left DLPFC in patients and controls separated for rs12364283 genotype (below).

Fig. 4

(A) Coronal and sagittal sections (images thresholded at P < 0.005, uncorrected) of the BOLD response of the multiple regression in patients with schizophrenia. The TGG (rs12364283, rs2283265 and rs1076560) haplotype has a positive relationship with BOLD activity in caudate during WM. (B) Coronal section and 3D rendering (images thresholded at P < 0.005, uncorrected) of the BOLD response of the multiple regression in controls. The TGG (rs12364283, rs2283265 and rs1076560) haplotype has a negative relationship with BOLD activity in caudate and prefrontal cortex during WM.

Fig. 5

Mean ± 0.95 CI of the interaction between WM behavioural performance and rs1076560 genotype.