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

Abstract Background Increased expression of the complement component 4A (C4A) gene is associated with a 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 the risk for psychotic symptoms in childhood. Here, we perform a multi-ancestry phenome-wide association study in 7789 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 is not related to childhood psychotic experiences, cognition, or global measures of brain structure, it is 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 a greater number and severity of psychosis-like events at 1-year and 2-year follow-up time points. 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.