Evidence for association of schizophrenia with genetic variation in the 8p21.3 gene, PPP3CC , encoding the calcineurin gamma subunit

Abstract

Schizophrenia is a severe psychiatric disorder characterized by a complex mode of inheritance. Forebrain-specific CNB knockout mice display a spectrum of behavioral abnormalities related to altered behaviors observed in schizophrenia patients. To examine whether calcineurin dysfunction is involved in schizophrenia etiology, we undertook studies of an initial subset of calcineurinrelated genes, prioritizing ones that map to loci previously implicated in schizophrenia by linkage studies. Transmission disequilibrium studies in a large sample of affected families detected association of the PPP3CC gene, which encodes the calcineurin ␥ catalytic subunit, with disease. Our results identify PPP3CC, located at 8p21.3, as a potential schizophrenia susceptibility gene and support the proposal that alterations in calcineurin signaling contribute to schizophrenia pathogenesis. S chizophrenia is a severe psychiatric condition that affects Ϸ1% of the population worldwide (1). Studies of the inheritance of schizophrenia have revealed that it is a multifactorial disease characterized by multiple genetic susceptibility elements, each contributing a modest increase in risk (2). Family linkage studies and studies of chromosomal abnormalities associated with schizophrenia have identified a number of schizophrenia susceptibility loci (2, 3). Such loci provide a basis for higher resolution genetic studies and a criterion for assessment of potential candidate genes. In addition to direct genetic analysis, a longstanding body of pharmacological studies has led to the prevailing hypotheses that dysfunction of dopaminergic or Nmethyl-D-aspartate (NMDA) receptor-mediated signaling are major contributing factors in schizophrenia pathogenesis (4-6).Calcineurin is a calcium-dependent serine͞threonine protein phosphatase that is highly expressed in the CNS (7,8). Calcineurin consists of a heterodimer composed of a regulatory subunit, CNB, and a catalytic subunit, CNA (7, 8). There are three different CNA isoforms encoded by distinct genes. Calcineurin activity plays a key role in the downstream regulation of dopaminergic signal transduction (9) and in the induction of certain forms of N-methyl-D-aspartate receptor-dependent synaptic plasticity (10, 11). Thus, calcineurin function could comprise a critical link between dopaminergic and glutamatergic signaling.In an accompanying study, we report that forebrain-specific CNB knockout mice display a spectrum of behavioral abnormalities that is strikingly reminiscent of altered behaviors observed in schizophrenia patients (12). Based on these findings, we decided to further investigate the potential involvement of calcineurin dysfunction in schizophrenia etiology by directly testing for genetic association of calcineurin-related candidate genes with schizophrenia. We prioritized examination of genes encoding calcineurin subunits or calcineurin-related molecules that map to schizophrenia susceptibility loci. We present direct genetic evidence for association of the PPP3CC gene with schizophrenia. PP...

More evidence supports the association of PPP3CC with schizophrenia

“…Comparing our SNP markers with the significant SNPs reported by Gerber's et al, 7 we had a wider range (from the promoter region to intron 12) of coverage in PPP3CC gene than did Gerber's SNPs (from exon 1 to intron 4). Distal to exon 1, the SNP of rs2272080 (primer ID 6577) showed statistical Table 2.…”

“…The 10 SNP markers used in this study covered a wide-enough genomic regions, ranging from the SLC39A14 gene close to the PPP3CC promoter region to the promoter region of the next SCAM-1 gene, with an average SNP marker distance of about 12.9 kb. One SNP, CCS3 (equal to primer ID 6555), was also used by Gerber et al 7 Significant associations had been demonstrated between SNP CCS3 and schizophrenia in the latter investigation (P = 0.041) but not in the present study (P = 0.33). Of the five PPP3CC SNPs screened by Gerber et al, 7 which covered the genomic regions from exon 1 (rs1049437) to intron 4 (rs2461491), their most significant SNP locus is at the intron 1 of CC21 (P = 0.038) close to our significant SNP 6577.…”

“…10 The PPP3CC subunit of CNA located on chromosome 8p21.3 has been reported to be associated with schizophrenia in American samples. 7 However, this result was not confirmed in other ethnic groups. 11 To assess further the association between PPP3CC and schizophrenia, we genotyped 10 single-nucleotide polymorphisms (SNPs) across the gene in 218 Taiwanese schizophrenia families with at least two affected siblings.…”

“…Failure to genotype the whole gene could result in a missed associated region and false negative results. 11 For this study, we selected two SNP markers (CC1a rs1049437 and CCS3 rs2461491) reported previously 7 with identification number released in NCBI and seven other SNPs across PPP3CC.…”

“…5 Differential expressions of these three CNA isoforms have been demonstrated in various areas of the brain. 6,7 The functional role of these CNA subunits in the brain is not clear; however, calcineurin may regulate the dopaminergic receptor signal transduction pathway 8 as well as synaptic efficiency through the NMDA receptors. 1 There are multiple behavior alterations mimicking the symptoms of schizophrenia in conditional CNB knockout mice.…”