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APOL2 – Schizophrenia

APOL2 is one of six apolipoprotein-L genes clustered on chromosome 22q12.3 and has been proposed as a positional and functional candidate for schizophrenia (Schizophrenia). The APOL gene family exhibits enriched expression in brain tissue, suggesting a potential role in neuronal lipid metabolism and neurodevelopment.

A case–control study of 219 cases and 231 controls found no significant association between SNPs in APOL2 or other APOL family genes and schizophrenia in an Irish cohort (PMID:15949655). In contrast, a family-based association study of 377 pedigrees (1,161 genotyped members, 647 affected) across African-American, European-American, Chinese, and Japanese families identified two APOL2 SNPs (rs9610449 and rs6000200) and corresponding haplotypes associated with risk in African-Americans (global p=0.00029) and in combined AA + EA samples (global p=0.0013) (PMID:18632255).

A reanalysis of schizophrenia GWAS data using ICSNPathway highlighted APOL2 among genes involved in estrogen biosynthetic processes, implying a mechanistic link to neuroendocrine pathways in schizophrenia (PMID:23644028). Functional evidence includes reported up-regulation of APOL2 expression in post-mortem schizophrenic brains and its putative role in steroid metabolism, but no in vitro or in vivo models have definitively established pathogenic mechanisms.

Overall, genetic association data for APOL2 in schizophrenia are limited and conflicting, lacking replication of findings and rare-variant segregation. Additional large-scale studies and functional validations are required. Key take-home: APOL2 remains a plausible but preliminarily supported susceptibility gene for schizophrenia, with insufficient evidence for clinical genetic testing at present.

References

  • Schizophrenia research • 2005 • Investigation of the apolipoprotein-L (APOL) gene family and schizophrenia using a novel DNA pooling strategy for public database SNPs PMID:15949655
  • Schizophrenia research • 2008 • Association of SNPs and haplotypes in APOL1, 2 and 4 with schizophrenia. PMID:18632255
  • Gene • 2013 • Pathway analysis of a genome-wide association study in schizophrenia. PMID:23644028

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Initial case–control study showed no association in 219 cases vs 231 controls ([PMID:15949655]); family-based study in 377 families ([PMID:18632255]) reported haplotype associations without consistent replication; pathway analysis ([PMID:23644028]) only indirectly implicates APOL2; evidence remains preliminary and conflicting.

Genetic Evidence

Limited

Common SNP and haplotype associations across cohorts ([PMID:18632255]) and negative case–control data ([PMID:15949655]) without rare variant or segregation data.

Functional Evidence

Limited

Up-regulation of APOL2 expression in postmortem brains ([PMID:15949655]) and its involvement in estrogen biosynthesis pathways from GWAS pathway analysis ([PMID:23644028]) provide preliminary mechanistic support.