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

Published online by Cambridge University Press:  09 January 2018

G. Donohoe ,
J. Holland ,
D. Mothersill ,
S. McCarthy-Jones ,
D. Cosgrove ,
D. Harold ,
A. Richards ,
K. Mantripragada ,
M. J. Owen  and
M. C. O'Donovan
...Show all authors
G. Donohoe*
Affiliation:
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
J. Holland
Affiliation:
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
D. Mothersill
Affiliation:
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
S. McCarthy-Jones
Affiliation:
Neuropsychiatric Genetics Research Group, Department of Psychiatry & Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland
D. Cosgrove
Affiliation:
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
D. Harold
Affiliation:
School of Biotechnology, Dublin City University, Dublin, Ireland
A. Richards
Affiliation:
MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, UK
K. Mantripragada
Affiliation:
MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, UK
M. J. Owen
Affiliation:
MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, UK
M. C. O'Donovan
Affiliation:
MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, UK
M. Gill
Affiliation:
Neuropsychiatric Genetics Research Group, Department of Psychiatry & Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland
A. Corvin
Affiliation:
Neuropsychiatric Genetics Research Group, Department of Psychiatry & Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland
D. W. Morris
Affiliation:
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
*
Author for correspondence: Professor G. Donohoe, E-mail: [email protected]
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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.

Keywords

Complement component 4memory functionMHC complexschizophreniatemporal cortex
Type
Original Articles
Information
Psychological Medicine , Volume 48 , Issue 10 , July 2018 , pp. 1608 - 1615
Copyright
Copyright © Cambridge University Press 2018 

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