Multi-ethnic, phenome-wide association of complement component 4 variation with psychiatric and brain developmental phenotypes in youth

Abstract Background: Increased expression of the complement component 4A (C4A) gene is associated with greater lifetime risk of schizophrenia. In the brain, C4A is involved in synaptic pruning; yet, it remains unclear the extent to which upregulation of C4A alters brain development or is associated with risk for psychotic symptoms in childhood. Here, we performed a multi-ethnic phenome-wide association study in 7,789 children aged 9-12 years to examine the relationship between genetically-regulated expression (GREx) of C4A, childhood brain structure, cognition, and psychiatric symptoms. Results: While C4A GREx was not related to childhood psychotic experiences, cognition, or global measures of brain structure, it was associated with a localized reduction in regional surface area (SA) of the entorhinal cortex. Furthermore, we show that reduced entorhinal cortex SA at 9-10 years predicts greater number and severity of psychosis-like events at 1-year and 2-year follow-up timepoints. We also demonstrate that the effects of C4A on the entorhinal cortex are independent of genome-wide polygenic risk for schizophrenia. Conclusions: Our results suggest neurodevelopmental effects of C4A on childhood medial temporal lobe structure, which may serve as a biomarker for schizophrenia risk prior to symptom onset.