Genetic evidence implicating DARPP-32 in human frontostriatal structure, function, and cognition

Abstract

Dopamine- and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32), encoded by PPP1R1B, is a pivotal integrator of information in dopaminoceptive neurons, regulating the response to neuroleptics, psychotomimetics, and drugs of abuse, and affecting striatal function and plasticity. Despite extensive preclinical work, there are almost no data on DARPP-32 function in humans. Here, we identify, through resequencing in 298 chromosomes, a frequent PPP1R1B haplotype predicting mRNA expression of PPP1R1B isoforms in postmortem human brain. This haplotype was associated with enhanced performance on several cognitive tests that depend on frontostriatal function. Multimodal imaging of healthy subjects revealed an impact of the haplotype on neostriatal volume, activation, and the functional connectivity of the prefrontal cortex. The haplotype was associated with the risk for schizophrenia in 1 family-based association analysis. Our convergent results identify a prefrontal-neostriatal system affected by variation in PPP1R1B and suggest that DARPP-32 plays a pivotal role in cognitive function and possibly in the pathogenesis of schizophrenia.

Figures

Figure 1. Genetic variation in the PPP1R1B region, showing the genotyped SNPs and their LD.

Top row shows relative positions of the SNPs (see Table 1 for numbering). Below is a color-coded display of LD: strong LD (D'), red; weak LD, pink; weaker LD, white; not calculated, blue boxes. The haplotype block defined by the method of Gabrieli et al. that was used for association with biological and clinical phenotypes is marked by a black outline (output of the program Haploview). See Tables 1 and 2 and DNA collection and genotyping in Methods for details.

Figure 2. Effect of PPP1R1B haplotype on mRNA expression in postmortem human brain.

(A) Exon position of primers used for quantitative PCR for isoform amplification, showing which isoform was amplified by which probe. (B) Effect of PPP1R1B haplotypes on mRNA expression for the common isoform. The PPP1R1B haplotype has an impact on expression of all probes assaying the expression of the full-length mRNA (type 14, P < 0.006; type 10, P = 0.09; type 9967, P < 0.003). Expression was highest for homozygotes of the frequent (CGCACTC) haplotype (21 subjects), lowest for carriers of the less frequent (GATGTCA) haplotype (11 subjects), and intermediate for 2 subjects heterozygous for CGCACTC in combination with a rare haplotype. B is the ratio of DARPP expression to the geometric mean of expression of 3 housekeeping genes. See Gene expression in Methods for details.

Figure 3. Neuroimaging analyses (structure and function) of common haplotype in PPP1R1B in control sample of white subjects.

Top row shows haplotype effects on volume (A) or activation (C and E) in striatum; bottom row shows haplotype effects on structural (B) and functional (D and F) connectivity of striatum with prefrontal cortex. Structural MRI analyses (voxel-based morphometry): (A) significantly reduced volume in striatum (P < 0.05) for carriers of the frequent (CGCACTC) haplotype; (B) greater structural connectivity between prefrontal cortex and striatum for homozygotes for the frequent (CGCACTC) haplotype. fMRI, N-back task: (C) significantly reduced reactivity in putamen (P < 0.05) for carriers of the frequent (CGCACTC) haplotype; (D) greater functional connectivity between prefrontal cortex and striatum for homozygotes for the frequent (CGCACTC) haplotype. fMRI, FMT: (E) significantly reduced reactivity in striatum (P < 0.05) for carriers of the frequent (CGCACTC) haplotype; (F) greater functional connectivity between prefrontal cortex and striatum for homozygotes for the frequent (CGCACTC) haplotype. t color scales depict statistical significance level (t statistical value). See Supplemental Tables 2–4 for detailed statistical information and Neuroimaging in Methods for methodological details.