G Donohoe1, J Holland1, D Mothersill1, S McCarthy-Jones2, D Cosgrove1, D Harold3, A Richards4, K Mantripragada4, M J Owen4, M C O'Donovan4, M Gill2, A Corvin2, D W Morris1. 1. The Cognitive Genetics & Cognitive Therapy Group,The School of Psychology and Discipline of Biochemistry,The Centre for Neuroimaging & Cognitive Genomics,National University of Ireland Galway,University Road,Galway,Ireland. 2. Neuropsychiatric Genetics Research Group,Department of Psychiatry & Institute of Molecular Medicine,Trinity College Dublin,Dublin,Ireland. 3. School of Biotechnology,Dublin City University,Dublin,Ireland. 4. MRC Centre for Neuropsychiatric Genetics and Genomics,Cardiff University School of Medicine,Cardiff,UK.
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.
BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.
Authors: Ashley L Comer; Tushare Jinadasa; Balaji Sriram; Rhushikesh A Phadke; Lisa N Kretsge; Thanh P H Nguyen; Giovanna Antognetti; James P Gilbert; Jungjoon Lee; Elena R Newmark; Frances S Hausmann; SaraAnn Rosenthal; Kevin Liu Kot; Yenyu Liu; William W Yen; Borislav Dejanovic; Alberto Cruz-Martín Journal: PLoS Biol Date: 2020-01-14 Impact factor: 8.029
Authors: Juan A Gallego; Emily A Blanco; Christopher Morell; Todd Lencz; Anil K Malhotra Journal: Neuropsychopharmacology Date: 2020-09-22 Impact factor: 7.853