Genetically predicted complement component 4A expression: effects on memory function and middle temporal lobe activation

• Published in: Psychological medicine 2018-07, Vol.48 (10), p.1608-1615
• Main Authors: Donohoe, G., Holland, J., Mothersill, D., McCarthy-Jones, S., Cosgrove, D., Harold, D., Richards, A., Mantripragada, K., Owen, M. J., O'Donovan, M. C., Gill, M., Corvin, A., Morris, D. W.
• Format: Article
• Language: English
• Subjects: Adult; Animal models; Brain; Cognition; Cognition & reasoning; Cognitive Dysfunction - diagnostic imaging; Cognitive Dysfunction - physiopathology; Complement C4a - metabolism; Complement component C4; Consortia; Cortex; Cortical activation; Female; Functional Neuroimaging; Gene Expression - genetics; Genetics; Genomes; Genomics; Humans; Information processing; Ireland; Learning; Magnetic Resonance Imaging; Major histocompatibility complex; Major Histocompatibility Complex - genetics; Male; Memory; Memory Disorders - diagnostic imaging; Memory Disorders - physiopathology; Memory, Short-Term - physiology; Mental disorders; Mental Recall - physiology; Middle Aged; Original Articles; Psychiatry; Psychosis; Psychotic Disorders - diagnostic imaging; Psychotic Disorders - genetics; Psychotic Disorders - physiopathology; Ribonucleic acid; RNA; Schizophrenia; Temporal lobe; Temporal Lobe - diagnostic imaging; Temporal Lobe - physiopathology; Temporal lobes; Therapeutic applications; Variants; Visual cortex; Visual processing; Working groups
• ISSN: 0033-2917; 1469-8978
• DOI: 10.1017/S0033291717002987

The longstanding association between the major histocompatibility complex (MHC) locus and schizophrenia (SZ) risk has recently been accounted for, partially, by structural variation at the complement component 4 (C4) gene. This structural variation generates varying levels of C4 RNA expression, and genetic information from the MHC region can now be used to predict C4 RNA expression in the brain. Increased predicted C4A RNA expression is associated with the risk of SZ, and C4 is reported to influence synaptic pruning in animal models. Based on our previous studies associating MHC SZ risk variants with poorer memory performance, we tested whether increased predicted C4A RNA expression was associated with reduced memory function in a large (n = 1238) dataset of psychosis cases and healthy participants, and with altered task-dependent cortical activation in a subset of these samples. We observed that increased predicted C4A RNA expression predicted poorer performance on measures of memory recall (p = 0.016, corrected). Furthermore, in healthy participants, we found that increased predicted C4A RNA expression was associated with a pattern of reduced cortical activity in middle temporal cortex during a measure of visual processing (p < 0.05, corrected). These data suggest that the effects of C4 on cognition were observable at both a cortical and behavioural level, and may represent one mechanism by which illness risk is mediated. As such, deficits in learning and memory may represent a therapeutic target for new molecular developments aimed at altering C4's developmental role.