Sex-specific effects of the rs9896243 single nucleotide polymorphism on verbal memory in first episode psychosis: A family-based approach.

Abstract

Background: Sex differences in verbal memory (VM) are well documented in schizophrenia spectrum disorders, with women typically outperforming men, especially in early illness stages. A previous genome-wide association study identified the SNP rs9896243 in the NSF gene as linked to VM performance in the general population. Here, we investigate its role in a family-based first-episode psychosis (FEP) cohort, focusing on interactions with sex and diagnostic status.

Methods: A total of 486 participants completed the Spanish version of Rey Auditory Verbal Learning Test (RAVLT). Mixed-effects models assessed associations between rs9896243 genotypes and VM outcomes, testing interactions by sex and clinical status. Variant functional annotation was carried out using the Variant Effect Predictor, with integrated eQTL and sQTL information derived from the Genotype-Tissue Expression (GTEx) project and gene enrichment analysis.

Results: Female C-allele carriers in the control and sibling groups showed significantly higher scores in immediate, short-delay, and long-delay recall tasks compared to males. However, this female advantage was not observed in FEP patients. Notably, male FEP patients carrying the C allele demonstrated the most pronounced recognition deficits. Functional annotation data implicated brain-region-specific regulation of ARL17A, MAPT, CRHR1, and KANSL1, genes involved in memory-related pathways.

Conclusions: Our findings extend previous genomic data identifying the role of NSF gene in VM performance by showing a sex-specific genetic influence of rs9896243 that differs between FEP patients and unaffected individuals, with female C-allele carriers outside the FEP group showing a better cognitive performance Although the functional annotations are exploratory and should be considered hypothesis-generating, they suggest that rs9896243 plays a role in brain regulatory networks essential for cognitive function, with potential implications for sex-informed early detection strategies in psychosis.