Complement Component 4 Shows Sex-Specific Effects on Adolescent Brain Structure Rate of Change

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The strongest common genetic association with schizophrenia is linked to increased expression of the complement component 4A (C4A) gene. In the brain, C4A expression is thought to influence synaptic pruning and to act in a sex-specific manner, contributing to a higher risk of schizophrenia in males compared to females. We previously demonstrated in a cohort of ~7,500 youth from the ABCD Study that increased genetically predicted C4 gene expression is associated with reduced surface area of the entorhinal cortex at 9–10 years of age, which predicts greater number and severity of psychosis-like experiences 1–2 years later (Hernandez, 2023). However, the impact of C4A expression on the rate of change (ROC) in brain structure during childhood and adolescence remains unclear. To address this, we investigated the relationship between genetically predicted C4A expression and longitudinal changes in regional brain surface area, cortical thickness, and volume in 2,977 ABCD participants with structural MRI data collected at three timepoints (ages 9–10, 11–12, and 13–14 years). Additionally, we conducted a phenome-wide association study (PheWAS) to evaluate associations between brain regions influenced by C4A expression and 138 psychiatric and behavioral traits assessed at 13–14 years.