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Abstract.

Background: 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.

Methods: We obtained genetic information and performance measures on seven cognitive tasks for up to 329 773 individuals from the UK Biobank, as well as brain imaging data for a subset of 33 003 participants. Direct genotypes for variants (n = 3213) within the major histocompatibility complex region were used to impute C4 structural variation, from which predicted expression of the C4A and C4B genes in human brain tissue were predicted. We investigated if predicted brain C4A or C4B expression were associated with cognitive performance and brain imaging measures using linear regression analyses.

Results: 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.

Conclusions: 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.