PPP3CC – Schizophrenia

PPP3CC is the gamma isoform of the calcineurin A catalytic subunit and has been investigated as a susceptibility gene in schizophrenia. In a family-based study of 218 Taiwanese sibling pairs, the untranslated‐region SNP rs2272080 showed nominal association with disease and correlated with increased PPP3CC expression in lymphoblastoid cell lines for TT and TG versus GG genotypes (PMID:17339875). A Japanese pedigree analysis of 124 families provided nominal replication of association at PPP3CC (PMID:17360599), and a meta-analysis across 12 candidate genes reported modest minor‐allele odds ratios of 1.072–1.121 for PPP3CC variants in combined samples (PMID:18715757). However, a large European case‐control cohort (1,870 cases, 2,002 controls) found no gene‐ or SNP‐wise significance for PPP3CC (PMID:18198266).

Functional evaluation is limited to eQTL analyses in lymphoblastoid cells, without in vivo models, segregation of rare variants, or rescue experiments. The absence of robust replication, lack of segregation data, and underpowered effect sizes yield inconsistent support for a causal role. Key take-home: current genetic and experimental evidence is insufficient to establish PPP3CC as a clinically actionable schizophrenia gene.

References

• Molecular psychiatry • 2007 • More evidence supports the association of PPP3CC with schizophrenia. PMID:17339875
• Proceedings of the National Academy of Sciences of the United States of America • 2007 • Genetic analysis of the calcineurin pathway identifies members of the EGR gene family, specifically EGR3, as potential susceptibility candidates in schizophrenia. PMID:17360599
• Schizophrenia research • 2008 • Genetic associations with schizophrenia: meta-analyses of 12 candidate genes. PMID:18715757
• The American journal of psychiatry • 2008 • No significant association of 14 candidate genes with schizophrenia in a large European ancestry sample: implications for psychiatric genetics. PMID:18198266

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