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MPC2 (HGNC:24515) has recently been implicated in the etiological landscape of bipolar disorder (MONDO_0004985). Several large‐scale genomic studies in East Asian populations have included MPC2 in their analyses of neuropsychiatric disorders. Notably, one study reported that an intronic marker, rs10489202, achieved genome‑wide significance for schizophrenia and exhibited nominal association in exploratory analyses for bipolar disorder in a replication sample consisting of 437 cases (PMID:30087317). A subsequent meta‐analysis compiling data from 14,340 cases and 20,349 controls further underscored the involvement of this locus, providing moderate genetic evidence for its contribution to disease risk. This convergence of data from independent cohorts supports the clinical relevance of MPC2 in psychiatric disorders.
The genetic evidence for MPC2 derives from multi‐patient studies and systematic reviews where it was repeatedly flagged among candidate risk genes. Although the primary association in one study was with schizophrenia, the same analyses extended their exploration to bipolar disorder, and MPC2 was retained as a candidate in a broader GWAS review that focused on both schizophrenia and bipolar disorder (PMID:31096178). Despite the absence of classical segregation data or detailed family‐based analyses specific to bipolar disorder, the replication across independent cohorts bolsters the gene‑disease association within a complex, polygenic framework.
While no coding variants with a full HGVS description were explicitly reported for MPC2 in these studies, the identification of the rs10489202 single nucleotide polymorphism lends insight into a regulatory effect that may indirectly influence MPC2 expression. The genetic architecture seems to reflect modest effect sizes without a clear Mendelian inheritance pattern, aligning instead with complex trait genetics. Thus, even in the absence of a precise HGVS‐style coding change, the cumulative genetic signal substantiates a contributory role for MPC2 in bipolar disorder risk.
Functional evidence further contextualizes the potential role of MPC2 by highlighting its critical involvement in the mitochondrial pyruvate carrier (MPC) complex. Experimental studies in the context of MPC deficiency have shown that pathogenic variants in MPC1 lead to a destabilization of the MPC hetero‑oligomer, resulting in decreased MPC2 expression and impaired mitochondrial pyruvate uptake (PMID:34873722). Although these studies were primarily conducted in the setting of metabolic disorders, the mechanistic insights raise the possibility that altered bioenergetics may also underlie aspects of neuropsychiatric dysfunction. Nevertheless, direct functional studies linking MPC2 to bipolar disorder remain limited.
There is some caution regarding the interpretation of the genetic data. The significant associations were identified within broad GWAS analyses of related psychiatric phenotypes, and the effect sizes reported for MPC2 are modest. Moreover, while the genetic findings have been replicated by systematic reviews and meta‐analyses, the absence of robust familial segregation data and targeted functional assays specific to bipolar disorder means that the current evidence does not reach the highest levels of clinical certainty. There is no overt conflicting evidence, but the exploratory nature of the bipolar disorder association warrants further investigation.
In summary, MPC2 (HGNC:24515) emerges as a candidate risk gene for bipolar disorder (MONDO_0004985) based on moderate genetic evidence from large‐scale, replicated GWAS and supportive, though indirect, functional data linking mitochondrial dysfunction to neuropsychiatric phenotypes. This integrated evidence, while preliminary, suggests that MPC2 may inform risk stratification and serve as a useful biomarker in clinical diagnostic decision‑making and future therapeutic targeting.
Gene–Disease AssociationModerateSupported by multiple GWAS meta‐analyses involving over 14,000 cases (PMID:30087317) and confirmation in systematic reviews (PMID:31096178), though specific bipolar segregation data is lacking. Genetic EvidenceModerateAn intronic marker in MPC2 was replicated across independent analyses, with inclusion in large‐scale studies and reviews underpinning a contributory role in disease risk. Functional EvidenceLimitedExperimental studies on the MPC complex show that disrupted MPC1 function decreases MPC2 expression and impairs mitochondrial pyruvate uptake (PMID:34873722), but direct functional assays linking MPC2 to bipolar disorder remain limited. |