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

  • G. Donohoe (a1), J. Holland (a1), D. Mothersill (a1), S. McCarthy-Jones (a2), D. Cosgrove (a1), D. Harold (a3), A. Richards (a4), K. Mantripragada (a4), M. J. Owen (a4), M. C. O'Donovan (a4), WTCCC2, M. Gill (a2), A. Corvin (a2) and D. W. Morris (a1)...



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.


Corresponding author

Author for correspondence: Professor G. Donohoe, E-mail:


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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, F209F216.
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, 467479.
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, 223238.
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.
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, 471475.
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, 578579.
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, 203209.
Eickhoff, SB, Heim, S, Zilles, K and Amunts, K (2006) Testing anatomically specified hypotheses in functional imaging using cytoarchitectonic maps. NeuroImage 32, 570582.
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, 511521.
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, 13251335.
First, MB (2005) Structured Clinical Interview for DSM-IV-TR Axis I Disorders: Patient Edition. New York: Biometrics Research Department, Columbia University.
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.
Grosbras, MH and Paus, T (2006) Brain networks involved in viewing angry hands or faces. Cerebral Cortex 16, 10871096.
Hakobyan, S, Boyajyan, A and Sim, RB (2005) Classical pathway complement activity in schizophrenia. Neuroscience Letters 374, 3537.
Heinrichs, RW and Zakzanis, KK (1998) Neurocognitive deficit in schizophrenia: a quantitative review of the evidence. Neuropsychology 12, 426.
IBM Corp (2012) IBM SPSS Statistics for Windows, Version 21.0. New York: IBM Corp Armonk.
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, 377382.
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, 620628.
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, 7785.
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, 225230.
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, 189195.
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, 748752.
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, 11501159.
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, 266281.
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, 296303.
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, 530537.
Rudduck, C, Beckman, L, Franzen, G, Jacobsson, L and Lindström, L (1985) Complement factor C4 in schizophrenia. Human Heredity, 35, 223226.
Schizophrenia Working Group of the Psychiatric Genomics Consortium (2014) Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421427.
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, 177183.
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, 753757.
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, 692700.
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, 877885.
Wechsler, D (1997) Wechsler Memory Scale (WMS-III). San Antonio, TX: Psychological Corporation.
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, 27342745.
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, 697706.



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