Hostname: page-component-cd9895bd7-gbm5v Total loading time: 0 Render date: 2024-12-26T18:52:08.774Z Has data issue: false hasContentIssue false
  • English
  • Français

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]
Get access Rights & Permissions [Opens in a new window]

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 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Athanasiu, L, Giddaluru, S, Fernandes, C, Christoforou, A, Reinvang, I, Lundervold, AJ, Nilsson, LG, Kauppi, K, Adolfsson, R, Eriksson, E, Sundet, K, Djurovic, S, Espeseth, T, Nyberg, L, Steen, VM, Andreassen, OA and Le Hellard, S (2017) A genetic association study of CSMD1 and CSMD2 with cognitive function. Brain Behavior and Immunity 61, F209–F216.Google Scholar
Carvajal, F, Rubio, S, Serrano, JM, Ríos-Lago, M, Alvarez-Linera, J, Pacheco, L and Martín, P (2013) Is a neutral expression also a neutral stimulus? A study with functional magnetic resonance. Experimental Brain Research 228, 467–479.Google Scholar
Cornblatt, BA, Risch, NJ, Faris, G, Friedman, D and Erlenmeyer-Kimling, L (1988) The Continuous Performance Test, identical pairs version (CPT-IP): I. New findings about sustained attention in normal families. Psychiatry Research 26, 223–238.Google Scholar
Dickie, EW, Tahmasebi, A, French, L, Kovacevic, N, Banaschewski, T, Barker, GJ, Bokde, A, Büchel, C, Conrod, P and Flor, H (2014) Global genetic variations predict brain response to faces. PLoS Genetics 10, e1004523.Google Scholar
Donohoe, G, Hayden, J, McGLADE, N, O'GRÁDA, C, Burke, T, Barry, S, Behan, C, Dinan, TG, O'Callaghan, E and Gill, M (2009) Is “clinical” insight the same as “cognitive” insight in schizophrenia? Journal of the International Neuropsychological Society 15, 471–475.CrossRefGoogle Scholar
Donohoe, G, Morris, DW, Robertson, IH, Clarke, S, McGhee, KA, Schwaiger, S, Nangle, JM, Gill, M and Corvin, A (2007) Variance in facial recognition performance associated with BDNF in schizophrenia. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 144, 578–579.Google Scholar
Donohoe, G, Walters, J, Hargreaves, A, Rose, E, Morris, DW, Fahey, C, Bellini, S, Cummins, E, Giegling, I and Hartmann, A (2013) Neuropsychological effects of the CSMD1 genome-wide associated schizophrenia risk variant rs10503253. Genes, Brain and Behavior 12, 203–209.CrossRefGoogle ScholarPubMed
Eickhoff, SB, Heim, S, Zilles, K and Amunts, K (2006) Testing anatomically specified hypotheses in functional imaging using cytoarchitectonic maps. NeuroImage 32, 570–582.CrossRefGoogle ScholarPubMed
Eickhoff, SB, Paus, T, Caspers, S, Grosbras, MH, Evans, AC, Zilles, K and Amunts, K (2007) Assignment of functional activations to probabilistic cytoarchitectonic areas revisited. NeuroImage 36, 511–521.Google Scholar
Eickhoff, SB, Stephan, KE, Mohlberg, H, Grefkes, C, Fink, GR, Amunts, K and Zilles, K (2005) A new SPM toolbox for combining probabilistic cytoarchitectonic maps and functional imaging data. NeuroImage 25, 1325–1335.CrossRefGoogle ScholarPubMed
First, MB (2005) Structured Clinical Interview for DSM-IV-TR Axis I Disorders: Patient Edition. New York: Biometrics Research Department, Columbia University.Google Scholar
Fusar-Poli, P, Placentino, A, Carletti, F, Landi, P, Allen, P, Surguladze, S, Benedetti, F, Abbamonte, M, Gasparotti, R and Barale, F (2009) Functional atlas of emotional faces processing: a voxel-based meta-analysis of 105 functional magnetic resonance imaging studies. Journal of Psychiatry and Neuroscience: JPN 34, 418.Google Scholar
Grosbras, MH and Paus, T (2006) Brain networks involved in viewing angry hands or faces. Cerebral Cortex 16, 1087–1096.Google Scholar
Hakobyan, S, Boyajyan, A and Sim, RB (2005) Classical pathway complement activity in schizophrenia. Neuroscience Letters 374, 35–37.Google Scholar
Heinrichs, RW and Zakzanis, KK (1998) Neurocognitive deficit in schizophrenia: a quantitative review of the evidence. Neuropsychology 12, 426.Google Scholar
IBM Corp (2012) IBM SPSS Statistics for Windows, Version 21.0. New York: IBM Corp Armonk.Google Scholar
Ille, R, Holl, AK, Kapfhammer, H-P, Reisinger, K, Schäfer, A and Schienle, A (2011) Emotion recognition and experience in Huntington's disease: is there a differential impairment? Psychiatry Research 188, 377–382.Google Scholar
Irish Schizophrenia Consortium, The Wellcome trust Case Control Consortium 2 (2012) Genome-wide association study implicates HLA-C* 01: 02 as a risk factor at the major histocompatibility complex locus in schizophrenia. Biological Psychiatry 72, 620–628.CrossRefGoogle Scholar
Lee, E, Kang, JI, Park, IH, Kim, J-J and An, SK (2008) Is a neutral face really evaluated as being emotionally neutral? Psychiatry Research 157, 77–85.CrossRefGoogle ScholarPubMed
Mothersill, O, Morris, DW, Kelly, S, Rose, EJ, Bokde, A, Reilly, R, Gill, M, Corvin, AP and Donohoe, G (2014 a). Altered medial prefrontal activity during dynamic face processing in schizophrenia spectrum patients. Schizophrenia Research 157, 225–230.Google Scholar
Mothersill, O, Morris, DW, Kelly, S, Rose, EJ, Fahey, C, O'Brien, C, Lyne, R, Reilly, R, Gill, M and Corvin, AP (2014 b). Effects of MIR137 on fronto-amygdala functional connectivity. NeuroImage 90, 189–195.Google Scholar
Purcell, SM, Wray, NR, Stone, JL, Visscher, PM, O'Donovan, MC, Sullivan, PF, Sklar, P, Ruderfer, DM, McQuillin, A and Morris, DW (2009) Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460, 748–752.Google Scholar
Ripke, S, O'Dushlaine, C, Chambert, K, Moran, JL, Kähler, AK, Akterin, S, Bergen, SE, Collins, AL, Crowley, JJ and Fromer, M (2013) Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nature Genetics 45, 1150–1159.CrossRefGoogle ScholarPubMed
Robbins, T, James, M, Owen, A, Sahakian, B, McInnes, L and Rabbitt, P (1994) Cambridge Neuropsychological Test Automated Battery (CANTAB): a factor analytic study of a large sample of normal elderly volunteers. Dementia and Geriatric Cognitive Disorders 5, 266–281.CrossRefGoogle ScholarPubMed
Rose, EJ, Morris, DW, Fahey, C, Robertson, IH, Greene, C, O'Doherty, J, Newell, FN, Garavan, H, McGrath, J, Bokde, A, Tropea, D, Gill, M, Corvin, AP and Donohoe, G (2012) The effect of the neurogranin schizophrenia risk variant rs12807809 on brain structure and function. Twin Research and Human Genetics 15, 296–303.Google Scholar
Rose, EJ, Morris, DW, Hargreaves, A, Fahey, C, Greene, C, Garavan, H, Gill, M, Corvin, A and Donohoe, G (2013) Neural effects of the CSMD1 genome-wide associated schizophrenia risk variant rs10503253. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 162, 530–537.Google Scholar
Rudduck, C, Beckman, L, Franzen, G, Jacobsson, L and Lindström, L (1985) Complement factor C4 in schizophrenia. Human Heredity, 35, 223–226.Google Scholar
Schizophrenia Working Group of the Psychiatric Genomics Consortium (2014) Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421–427.Google Scholar
Sekar, A, Bialas, AR, de Rivera, H, Davis, A, Hammond, TR, Kamitaki, N, Tooley, K, Presumey, J, Baum, M and Van Doren, V (2016) Schizophrenia risk from complex variation of complement component 4. Nature 530, 177–183.Google Scholar
Shi, J, Levinson, DF, Duan, J, Sanders, AR, Zheng, Y, Pe'Er, I, Dudbridge, F, Holmans, PA, Whittemore, AS and Mowry, BJ (2009) Common variants on chromosome 6p22. 1 are associated with schizophrenia. Nature 460, 753–757.Google Scholar
Walters, JT, Corvin, A, Owen, MJ, Williams, H, Dragovic, M, Quinn, EM, Judge, R, Smith, DJ, Norton, N and Giegling, I (2010) Psychosis susceptibility gene ZNF804A and cognitive performance in schizophrenia. Archives of General Psychiatry 67, 692–700.Google Scholar
Walters, JT, Rujescu, D, Franke, B, Giegling, I, Vásquez, AA, Hargreaves, A, Russo, G, Morris, DW, Hoogman, M and Da Costa, A (2013) The role of the major histocompatibility complex region in cognition and brain structure: a schizophrenia GWAS follow-up. American Journal of Psychiatry 170, 877–885.Google Scholar
Wechsler, D (1997) Wechsler Memory Scale (WMS-III). San Antonio, TX: Psychological Corporation.Google Scholar
Yang, Y, Chung, EK, Zhou, B, Blanchong, CA, Yu, CY, Füst, G, Kovacs, M, Vatay, A, Szalai, C, Karadi, I and Varga, L (2003) Diversity in intrinsic strengths of the human complement system: serum C4 protein concentrations correlate with C4 gene size and polygenic variations, hemolytic activities, and body mass index. The Journal of Immunology 171, 2734–2745.Google Scholar
Zhang, C, Lv, Q, Fan, W, Tang, W and Yi, Z (2017) Influence of CFH gene on symptom severity of schizophrenia. Neuropsychiatric Disease and Treatment 13, 697–706.CrossRefGoogle ScholarPubMed