The impact of CNV burden on age at onset of schizophrenia

BACKGROUND: Schizophrenia (SCZ) is a severe neuropsychiatric disorder with a complex genetic architecture influenced by both common and rare variants. Disease age at onset (AAO) is a critical clinical feature, with earlier onset associated with greater severity and poorer functional outcomes. While copy number variants (CNVs) are well-established contributors to SCZ risk, their role in modulating AAO remains less explored. METHODS: This study investigates the association between CNV burden and CNV length with AAO, leveraging a cohort of 836 individuals, including 323 patients with SCZ (31.6% female) and 513 healthy controls (52.1% female). RESULTS: Patients with SCZ exhibited a significantly higher CNV burden than the control group (P = 9.3e-03). Linear regression analyses revealed that the number of deletions, but not duplications, was significantly associated with earlier AAO (P = 9.28e-04). Patients with earlier onset of the disorder had the highest CNV load, with a trend toward decreasing burden with increasing AAO. CONCLUSIONS: These findings suggest that an increased burden of CNV deletions may disrupt neurodevelopmental pathways, contributing to earlier onset of SCZ. This study highlights the importance of CNV burden in elucidating the genetic architecture underlying SCZ and AAO, and emphasizes the value of using genetic tests to detect CNVs in informing future therapeutic approaches.