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

Kevin S O'Connell*, Ida E Sønderby, Oleksandr Frei, Dennis van der Meer, Lavinia Athanasiu, Olav B Smeland, Dag Alnæs, Tobias Kaufmann, Lars T Westlye, Vidar M Steen, Ole A Andreassen, Timothy Hughes, Srdjan Djurovic

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

4 Citations (Web of Science)



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.

Original languageEnglish
Pages (from-to)3497–3507
Number of pages11
JournalPsychological Medicine
Issue number15
Early online date3 Mar 2021
Publication statusPublished - Nov 2022


  • CSMD1
  • Cognition
  • GENE
  • immune system
  • major histocompatibility complex
  • mental health
  • psychiatric disorder
  • schizophrenia

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