Association between complement component 4A expression, cognitive performance and brain imaging measures in UK Biobank

Altered expression of the complement component C4A gene is a known risk factor for schizophrenia. Further, predicted brain C4A expression has also been associated with memory function highlighting that altered C4A expression in the brain may be relevant for cognitive and behavioral traits. We investigated if predicted brain C4A expression was associated with cognitive performance and brain imaging measures in the UK Biobank. We identified significant negative associations between predicted C4A expression and performance on select cognitive tests, and significant associations with MRI-based cortical thickness and surface area in select regions. Finally, we observed significant inconsistent partial mediation of the effects of predicted C4A expression on cognitive performance, by specific brain structure measures. These results demonstrate that the C4 risk locus is associated with the central endophenotypes of cognitive performance and brain morphology, even when considered independently of other genetic risk factors and in individuals without mental or neurological disorders.