MPC2 and Schizophrenia

This summary details the association between MPC2 and schizophrenia, a relationship established primarily through large-scale genetic association studies in East Asian populations. Meta-analyses have shown genome‑wide significant associations with schizophrenia, with one study reporting significant findings in a combined sample of 3977 cases and 5589 controls (PMID:26899211), and another meta‑analysis expanding the case numbers to 14,340 with 20,349 controls (PMID:30087317). The overall clinical validity of this association falls within the ClinGen category of Strong given the substantial sample sizes and reproducibility of the findings across independent cohorts.

Genetic evidence primarily centers on the common risk allele rs10489202 in MPC2, which has been repeatedly implicated in schizophrenia in these large cohorts. Although information on a specific HGVS‑annotated coding variant is not available from the reports, the robust statistical associations across thousands of subjects lend significant weight to the genetic data. There is no documented data on familial segregation in these studies, consistent with the complex, polygenic nature of schizophrenia.

In contrast, a replication study involving 1093 schizophrenia cases and 1022 controls failed to demonstrate a significant association for MPC2 variants (PMID:23933155). This conflicting evidence highlights the challenges of replication in complex disorders, but the negative result from a smaller cohort is outweighed by the robust findings from larger meta‑analyses.

Functional studies further support the biological importance of MPC2 by confirming its role as an essential partner with MPC1 in forming the mitochondrial pyruvate carrier complex (PMID:34873722). Although these studies primarily address cellular metabolism and do not directly link MPC2 function to schizophrenia pathology, they underline the critical role of MPC2 in maintaining mitochondrial function, which may be relevant to neuronal energy homeostasis and signaling.

The integration of extensive genetic evidence and supportive, albeit indirect, functional data culminates in a strong overall gene‑disease association. While the direct mechanistic connection between MPC2’s metabolic role and schizophrenia requires further research, the existing statistical associations are compelling and are of substantial clinical utility for diagnostic decision‑making and risk stratification in the disease.

Key take‑home: MPC2 variations represent a robust genetic marker for schizophrenia risk in East Asian populations, underscoring the potential for improved diagnostic and therapeutic strategies.

References

• Schizophrenia research • 2016 • Replication of Han Chinese GWAS loci for schizophrenia via meta-analysis of four independent samples PMID:26899211
• Translational psychiatry • 2018 • Genetic association and meta-analysis of a schizophrenia GWAS variant rs10489202 in East Asian populations PMID:30087317
• Neuroscience letters • 2013 • Lack of association between MPC2 variants and schizophrenia in a replication study of Han Chinese PMID:23933155
• Journal of inherited metabolic disease • 2022 • Identification and characterization of novel MPC1 gene variants causing mitochondrial pyruvate carrier deficiency PMID:34873722

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