Schizophrenia risk from complex variation of complement component 4
Open accessAbstract
Schizophrenia is a heritable brain illness with unknown pathogenic mechanisms. Schizophrenia's strongest genetic association at a population level involves variation in the major histocompatibility complex (MHC) locus, but the genes and molecular mechanisms accounting for this have been challenging to identify. Here we show that this association arises in part from many structurally diverse alleles of the complement component 4 (C4) genes. We found that these alleles generated widely varying levels of C4A and C4B expression in the brain, with each common C4 allele associating with schizophrenia in proportion to its tendency to generate greater expression of C4A. Human C4 protein localized to neuronal synapses, dendrites, axons, and cell bodies. In mice, C4 mediated synapse elimination during postnatal development. These results implicate excessive complement activity in the development of schizophrenia and may help explain the reduced numbers of synapses in the brains of individuals with schizophrenia.
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Non-Bayesian alternatives such as disordered neuromodulation, disrupted synaptic pruning, or abnormal cortical dynamics can also account for similar schizophrenia symptom profiles without invoking probabilistic inference.
“Moreover, non-Bayesian alternatives—such as models based on disordered neuromodulation (Hu et al. 2015), disrupted synaptic pruning (Sekar et al. 2016), or abnormal cortical dynamics (Uhlhaas et al. 2009)—can also account for similar symptom profiles without invoking probabilistic inference.”
From The myth of the Bayesian brain (2025) · cites this paper as Sekar et al. 2016
The Discussion proposes excessive or inappropriate synaptic pruning as a possible mechanism for schizophrenia, particularly its age of onset and synapse loss. It does not show that a pruning-based model accounts for the similar symptom profiles invoked in the citing sentence. The other two alternatives have separate citations and are not attributed to this paper. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThere are 7 core aging-upregulated genes overlapping all brain regions, including Gfap, Serpina3n, and C4b.
“To identify core aging-upregulated genes, we looked for overlap in gene expression changes between all brain regions and identified 7 genes (Figure 2D), including markers of reactive as-trocytes, Gfap and Serpina3n (Zamanian et al., 2012), and a component of the complement cascade involved in synapse elimination, C4b (Sekar et al., 2016).”
From The aging astrocyte transcriptome from multiple regions of the mouse brain. (2018) · cites this paper as Sekar et al., 2016
GWAS signals have revealed unexpected insights into biological basis of complex disease, including complement in acute macular degeneration, synaptic pruning in schizophrenia, and autophagy in inflammatory bowel disease.
“Examples include the role of complement in the pathogenesis of acute macular degeneration38, synaptic pruning in schizophrenia64 and autophagy in inflammatory bowel disease65.”
From A brief history of human disease genetics (2020) · cites this paper as [64]
Similar functional descriptions have been reported for individual loci implicated in schizophrenia, cardiovascular disease, type 2 diabetes and Alzheimer's disease.
“Similar functional descriptions have been reported for individual loci implicated in schizo phrenia64, cardiovascular disease104, type 2 diabetes105 and Alzheimer’s disease106, among others.”
From A brief history of human disease genetics (2020) · cites this paper as [64]
Many of the genes whose pathological variation confers susceptibility to psychiatric disorders play fundamental roles in brain development.
“and indeed many of the genes whose pathological variation confers susceptibility to psychiatric disorders play fundamental roles in brain development 7-9 .”
From Developmental timing and critical windows for the treatment of psychiatric disorders (2016) · cites this paper as [9]
The neurobiological mechanisms by which genetic variation confers risk for these disorders remain largely unknown.
“However, the neurobiological mechanisms through which genetic variation imparts risk, both individually and in aggregate, are still largely unknown (4–6).”
From Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder (2018) · cites this paper as [5]
In SCZ, PRS showed a genome-wide significant association with upregulation of C4A.
“In SCZ, PRS shows the genome-wide significant association with upregulation of the established risk gene C4A (5).”
From Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder (2018) · cites this paper as [5]
Evidence supports hyperactive complement-mediated synaptic pruning in schizophrenia pathophysiology, presumably through microglia.
“Evidence supports hyperactive complement-mediated synaptic pruning in SCZ pathophysiology, presumably through microglia (5)”
From Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder (2018) · cites this paper as [5]
C4A is the top GWAS-supported and strongly upregulated risk gene for schizophrenia.
“the top GWAS-supported, and strongly upregulated, risk gene for SCZ (5).”
From Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder (2018) · cites this paper as [5]
Seven variants in the MHC region are significantly associated with schizophrenia in this cohort (p<10^-6).
“and seven variants in the MHC region around the HLA genes, also a region with extensive linkage to known causal variants associated with schizophrenia61.”
From Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia (2016) · cites this paper as [61]
A majority of structural variants are not detectable with current genotyping platforms.
“Lastly, we recognize that a majority of structural variants (SVs) are not detectable with current genotyping platforms 32.”
From Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects (2017) · cites this paper as [32]
Synapse pruning by microglia involves the classical complement pathway, with C1q tagging of synapses, opsonization by C3b, and subsequent phagocytosis by microglia.
“Studies of C1q, C4, C3, and CR3 knockout mice suggest that the mechanism of developmental synapse pruning in the retinogeniculate system involves C1q tagging of synapses, opsonization of synapses by C3b, and subsequent phagocytosis of synapses by microglia (Stevens et al., 2007; Schafer et al., 2012; Sekar et al., 2016; Fig. 3 A).”
From Microglia in Alzheimer’s disease (2018) · cites this paper as Sekar et al., 2016
There is a strong correlation between schizophrenia risk alleles and up-regulation of C4A expression (Spearman's ρ = 0.66, P < 10−16).
“we found a strong correlation between the risk alleles for SCZ and up-regulation of expression of C4A (complement component 4A; Spearman’s ρ = 0.66, P < 10−16).”
From Gene expression elucidates functional impact of polygenic risk for schizophrenia (2016) · cites this paper as [32]
Serious infections increase the risk of subsequently developing schizophrenia, and genetic risk factors for schizophrenia increase microglial phagocytosis of synapses, leading to the idea that schizophrenia is triggered by excessive microglial phagocytosis of synapses during adolescence, and one potential cause of this is increased endotoxin.
“Serious infections increase the risk of subsequently developing schizophrenia [110], and genetic risk factors for schizophrenia increase microglial phagocytosis of synapses [111], leading to the idea that schizophrenia is triggered by excessive microglial phagocytosis of synapses during adolescence [111], and one potential cause of this is increased endotoxin.”
From The endotoxin hypothesis of neurodegeneration (2019) · cites this paper as [111]
The Ccl4 antibody's specificity was verified using secondary-antibody-only controls and preadsorption with recombinant Ccl4 protein, following a previously described method.
“Ccl4 antibody specificity was tested using secondary antibody only controls as well as with antibody preadsorption using recombinant Ccl4 protein, as previously described (Sekar et al., 2016).”
From Complex cell-state changes revealed by single cell RNA sequencing of 76,149 microglia throughout the mouse lifespan and in the injured brain (2018) · cites this paper as Sekar et al., 2016
In neurodevelopmental disorders, microglia can have impaired pruning or secrete molecules that contribute to CNS hyperactivity.
“Although not as clear in neurodevelopmental disorder, microglia can have impaired pruning or secrete molecules that contribute to hyperactivity in the CNS [7, 9].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [7]
Microglial dysfunction contributes to the pathogenesis of neurodegenerative disorders including Alzheimer's disease and neurodevelopmental disorders including autism spectrum disorder and schizophrenia.
“Microglial dysfunction contributes to the pathogenesis of neurodegenerative disorders including Alzheimer’s disease (AD) and neurodevelopmental disorders including autism spectrum disorder and schizophrenia [5-7].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [7]
There is substantial region-dependence in the magnitude and timing of C4b expression.
“For instance, we found substantial region-dependence in the magnitude and timing of C4b expression (Figure 1E), a complement component and major schizophrenia risk factor (Sekar et al., 2016) that is robustly up-regulated in aged mice (Hahn et al., 2020) and models of neurodegeneration (Zhou et al., 2020).”
From Atlas of the aging mouse brain reveals white matter as vulnerable foci (2023) · cites this paper as Sekar et al., 2016
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- Authors
- Sekar, A., Bialas, A. R., de Rivera, H., Davis, A., Hammond, T. R., Kamitaki, N., Tooley, K., Presumey, J., Baum, M., Van Doren, V., Genovese, G., Rose, S. A., Handsaker, R. E., Schizophrenia Working Group of the Psychiatric Genomics Consortium, Daly, M. J., Carroll, M. C., Stevens, B., & McCarroll, S. A.
- Affiliations
- Broad Institute (US)
- Boston Children's Hospital (US)
- Corresponding author
- McCarroll, Steven A.
- ORCID
- Venue
- Nature
- Published
- 2016-01-27
- Volume
- 530
- Issue
- 7589
- Pages
- 177-183
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4752392
- OpenAlex
- W2255138985
- Cited by
- 2,394
- References
- 56
- Citations by year
- 2026: 177 · 2025: 185 · 2024: 202 · 2023: 212 · 2022: 215 · 2021: 261 · 2020: 251 · 2019: 236 · 2018: 241 · 2017: 233 · 2016: 171 · 2015: 3 · 2014: 1 · 2012: 1
- FWCI
- 224.40
- Type
- journal article
- Language
- en
- Update notices
- correction (2021-12-15)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- VU Research Portal (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (acceptedVersion)
- Lancaster EPrints (Lancaster University) (acceptedVersion)
- Pure Amsterdam UMC (submittedVersion, other-oa)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Research Publications (Maastricht University) (submittedVersion, cc-by)
- eScholarship (California Digital Library) (submittedVersion)
- Institutional Research Information System (Università degli Studi di Trento) (submittedVersion)
- Minerva Access (University of Melbourne) (submittedVersion)
- Lirias (submittedVersion)
- GRO (submittedVersion, cc-by)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Research Portal (Queen's University Belfast) (submittedVersion)
- UCrea (University of Cantabria) (submittedVersion, cc-by)
- Research Publications (Maastricht University) (submittedVersion)
- NOVA (University of Newcastle Australia) (submittedVersion)
- Funders
- National Institute for Health and Care Research (PDA/02/06/016)
- Lundbeckfonden (R155-2014-1724)
- Medical Research Council (MR/P005748/1, MR/L010305/1)
- National Institute of Mental Health (R01MH042191, R01MH077139, U01MH105641, R01MH085548)
- National Human Genome Research Institute (R01HG006855, T32HG002295)
- National Institute of General Medical Sciences (T32GM007753)
- National Institute of Allergy and Infectious Diseases (T32AI074549)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD090255)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- schizophrenia, complement C4, C4A, C4b, major histocompatibility complex, genetic association, synaptic pruning, classical complement pathway, brain gene expression, mouse model
- MeSH terms
- Alleles, Amino Acid Sequence, Animals, Axons, Base Sequence, Brain, Complement Pathway, Classical, Complement C4, Dendrites, Gene Expression Regulation, Haplotypes, Humans, Major Histocompatibility Complex, Neuronal Plasticity, Risk Factors, RNA, Messenger, Schizophrenia, Synapses, Genetic Variation, Gene Dosage, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Models, Animal, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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