Children with Early-Onset Psychosis Have Increased Burden of Rare GRIN2A Variants

Abstract

Background: Children and adolescents with early-onset psychosis (EOP) have more rare genetic variants than individuals with adult-onset forms of the illness, implying that fewer EOP participants are needed for genetic discovery. The Schizophrenia Exome Sequencing Meta-analysis (SCHEMA) study predicted that 10 genes with ultra-rare variation were linked to adult-onset schizophrenia. We hypothesized that rare variants predicted “High” and “Moderate” by the Variant Effect Predictor Algorithm (abbreviated as VEPHMI) in these 10 genes would be enriched in our EOP cohort. Methods: We compared rare VEPHMI variants in individuals with EOP (N = 34) with race- and sex-matched controls (N = 34) using the sequence kernel association test (SKAT). Results: GRIN2A variants were significantly increased in the EOP cohort (p = 0.004), with seven individuals (20% of the EOP cohort) carrying a rare VEPHMI variant. The EOP cohort was then compared to three additional control cohorts. GRIN2A variants were significantly increased in the EOP cohort for two of the additional control sets (p = 0.02 and p = 0.02), and trending towards significance for the third (p = 0.06). Conclusion: Despite a small sample size, GRIN2A VEPHMI variant burden was increased in a cohort of individuals with EOP in comparison to controls. GRIN2A variants have been associated with a range of neuropsychiatric disorders including adult-onset psychotic spectrum disorder and childhood-onset schizophrenia. This study supports the role of GRIN2A in EOP and emphasizes its role in neuropsychiatric disorders.

Implications of SNP-triggered miRNA dysregulation in Schizophrenia development

“…Furthermore, the variants rs7206256 and rs11644461 in GRIN2A have been shown to be involved in early onset SCZ in Russian and Serbian populations (Poltavskaya et al, 2021). In an American study that included subjects from diverse backgrounds, it was observed that these identical variants were notably more prevalent in the early onset psychosis group when compared to the control subjects (Hojlo et al, 2023). Although the studies describe variants in GRIN2A to increase SCZ risk they do not specify how these variants affect gene function and expression.…”