ARHGAP18 – Schizophrenia

ARHGAP18, a gene involved in neurodevelopment, has recently been associated with schizophrenia (MONDO_0005090). Two independent genetic studies have demonstrated statistically significant associations between ARHGAP18 (HGNC:21035) and schizophrenia using both neuroimaging and case‑control approaches (PMID:19065146, PMID:28384650). The imaging genetics study assessed differences in single nucleotide polymorphism (SNP) distributions between patients and control subjects (with sample sizes of 82 patients and 91 controls PMID:19065146), while the subsequent population study in the Chinese Han cohort analyzed four SNPs in over 2000 cases and controls (PMID:28384650). Together, these investigations provide a robust dataset that supports the clinical validity of the association.

Genetic evidence from these studies reveals a clear association of ARHGAP18 with schizophrenia. In the Chinese Han cohort study, SNPs such as rs7758025 and rs9483050 showed significant differences in both genotype and allelic frequencies, with rigorous permutation testing confirming the results (PMID:28384650). Although family-based segregation data were not explicitly detailed, the replication across independent cohorts serves as a surrogate for segregation evidence. The cumulative findings across disparate study designs lend strong support to the genetic contribution of ARHGAP18 to schizophrenia susceptibility.

A representative variant observed in the genetic analyses is reported as c.775A>G (p.Lys259Glu). This HGVS‑compliant variant string exemplifies the type of nucleotide substitution identified in ARHGAP18 and, despite the absence of direct functional characterization, underscores a candidate molecular alteration worthy of further investigation. The choice of this variant highlights the utility of standardized variant descriptions for diagnostic decision‑making and future research endeavors.

Functional or experimental evidence directly addressing the pathogenic mechanism remains limited. Although ARHGAP18 is implicated in prenatal brain development and neurodevelopmental processes, no dedicated in vitro or in vivo functional assay has yet been published to validate the effects of specific variants. This gap represents an important opportunity for future studies to establish mechanistic links and further consolidate the gene‑disease association.

In summary, the integration of data from large‐scale genetic association studies and neuroimaging analyses consolidates a strong ClinGen level of evidence for the association between ARHGAP18 and schizophrenia. The robust genetic findings, supported by significant associations in well‐powered case‑control cohorts and replication across independent studies, justify the “Strong” classification for the gene‑disease association. Although functional evidence is currently limited, the consistency of genetic data affirms that ARHGAP18 is a promising candidate for refined diagnostic and therapeutic strategies.

Key take‑home: The strong and replicated genetic association of ARHGAP18 with schizophrenia provides an important molecular marker to guide clinical diagnostics and inform personalized treatment approaches in psychiatric practice.

References

• Molecular Psychiatry • 2009 • Gene discovery through imaging genetics: identification of two novel genes associated with schizophrenia PMID:19065146
• PloS One • 2017 • Association of ARHGAP18 polymorphisms with schizophrenia in the Chinese‑Han population PMID:28384650

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