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MSI2 has emerged as a promising candidate gene in the genetic architecture of schizophrenia. Multiple studies in Han Chinese populations have provided evidence supporting the association between MSI2 and schizophrenia through both common variant analysis and family‐based de novo mutation assessments. The initial genome-wide association study followed by a replication study demonstrated that several single-nucleotide polymorphisms in MSI2 showed significant differences in allele and genotype frequencies between schizophrenia patients and controls (PMID:27059221). The study design, which included 921 cases and 1244 controls, reinforces the importance of MSI2 in this complex disorder. These findings have spurred further investigation into the potential pathogenic contribution of MSI2 variants in neurodevelopment.
The replication study reported statistically significant associations for SNPs rs9892791 and rs11657292 along with rs1822381 after rigorous Bonferroni correction. Although the SNP designations are not described by a standard HGVS coding sequence, the robust statistical significance supports a role for MSI2 in schizophrenia risk. In parallel, a family-based study involving 23 families used whole-genome sequencing to identify an excess burden of de novo mutations in several neurodevelopment-associated genes, including MSI2 (PMID:32873781). This approach provided an additional layer of genetic evidence by demonstrating that the mutation load in MSI2 is elevated in affected individuals compared to unaffected siblings. These complementary methodologies underscore the multifaceted genetic contributions to schizophrenia.
The overall genetic evidence for the MSI2–schizophrenia association can be considered strong. The combined findings from large-scale case-control studies and family-based sequencing have identified significant associations and a higher burden of de novo alterations, respectively. Even though a classic segregation analysis of extended pedigrees was not a primary focus, the cumulative data from unrelated probands and family cohorts contribute to a statistically robust gene-disease association. The genetic studies were conducted with rigorous statistical corrections and included sizeable samples that minimize the likelihood of spurious associations. This robust dataset supports the assignment of a strong genetic evidence score for MSI2 in schizophrenia.
In contrast to the genetic studies, the current functional evidence directly linking MSI2 to schizophrenia remains limited. Several functional studies in related fields, such as neurogenesis, suggest that MSI2 plays key roles in stem-cell maintenance and differentiation. However, experimental models specifically replicating the schizophrenia phenotype—by interrogating altered neurogenesis in neuronal cells—are scarce. It is anticipated that future studies employing cellular or animal models of schizophrenia will further clarify the mechanistic underpinnings of MSI2 dysfunction in this context. As a result, the functional evidence score is tempered by the indirect nature of the current experimental data.
Integrating both strands of evidence, the genetic findings strongly support an association between MSI2 and schizophrenia, while the functional assays provide a biological rationale that warrants further exploration. The convergence of not only common variant associations but also de novo mutation burden analysis offers a coherent narrative that links MSI2 variants to altered neurodevelopmental trajectories potentially contributing to the disease. Although additional experimental data specific to neuronal function would enrich the understanding of pathogenic mechanisms, the available evidence is sufficient to consider MSI2 a significant susceptibility gene for schizophrenia.
Key take‐home: Robust genetic evidence supports the clinical utility of screening MSI2 in schizophrenia risk assessment, although additional functional studies are needed to fully elucidate the underlying pathogenic mechanisms.
Gene–Disease AssociationStrongGWAS replication in 921 cases and 1244 controls (PMID:27059221) and a burden test in 23 families demonstrating excess de novo mutations (PMID:32873781) support a strong overall association. Genetic EvidenceStrongMultiple independent studies, including case-control and family-based analyses, have identified significant SNP associations and de novo mutation burdens involving MSI2 in schizophrenia. Functional EvidenceLimitedAlthough MSI2 is known to influence neurogenesis and stem-cell maintenance, direct functional assays linking MSI2 dysfunction to schizophrenia-specific neurobiological phenotypes are still lacking. |