Schizophrenia risk from complex variation of complement component 4
Aswin Sekar, Allison R Bialas, Heather de Rivera, Avery Davis, Timothy R Hammond, Nolan Kamitaki, Katherine Tooley, Jessy Presumey, Matthew Baum, Vanessa Van Doren, Giulio Genovese, Samuel A Rose, Robert E Handsaker, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Mark J Daly, Michael C Carroll, Beth Stevens, Steven A McCarroll
Abstract
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.
Figures
References
- Cannon TD, et al. Cortex mapping reveals regionally specific patterns of genetic and disease-specific gray-matter deficits in twins discordant for schizophrenia. Proceedings of the National Academy of Sciences of the United States of America. 2002;99:3228–3233.
- Cannon TD, et al. Progressive reduction in cortical thickness as psychosis develops: a multisite longitudinal neuroimaging study of youth at elevated clinical risk. Biological psychiatry. 2015;77:147–157.
- Garey LJ, et al. Reduced dendritic spine density on cerebral cortical pyramidal neurons in schizophrenia. J Neurol Neurosurg Psychiatry. 1998;65:446–453.
- Glantz LA, Lewis DA. Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Arch Gen Psychiatry. 2000;57:65–73.
- Glausier JR, Lewis DA. Dendritic spine pathology in schizophrenia. Neuroscience. 2013;251:90–107.
- Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511:421–427.
- Shi J, et al. Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature. 2009;460:753–757.
- Stefansson H, et al. Common variants conferring risk of schizophrenia. Nature. 2009;460:744–747.
- International Schizophrenia Consortium et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature. 2009;460:748–752.
- Schizophrenia Psychiatric Genome-Wide Association Study Consortium. Genome-wide association study identifies five new schizophrenia loci. Nature genetics. 2011;43:969–976.
- Howson JM, Walker NM, Clayton D, Todd JA. Confirmation of HLA class II independent type 1 diabetes associations in the major histocompatibility complex including HLA-B and HLA-A. Diabetes Obes Metab. 2009;11(Suppl 1):31–45.
- Raychaudhuri S, et al. Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nature genetics. 2012;44:291–296.
- Escudero-Esparza A, Kalchishkova N, Kurbasic E, Jiang WG, Blom AM. The novel complement inhibitor human CUB and Sushi multiple domains 1 (CSMD1) protein promotes factor I-mediated degradation of C4b and C3b and inhibits the membrane attack complex assembly. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2013;27:5083–5093.
- Carroll MC, Campbell RD, Bentley DR, Porter RR. A molecular map of the human major histocompatibility complex class III region linking complement genes C4, C2 and factor B. Nature. 1984;307:237–241.
- Carroll MC, Belt T, Palsdottir A, Porter RR. Structure and organization of the C4 genes. Philos Trans R Soc Lond B Biol Sci. 1984;306:379–388.
- Dangel AW, et al. The dichotomous size variation of human complement C4 genes is mediated by a novel family of endogenous retroviruses, which also establishes species-specific genomic patterns among Old World primates. Immunogenetics. 1994;40:425–436.
- Horton R, et al. Variation analysis and gene annotation of eight MHC haplotypes: the MHC Haplotype Project. Immunogenetics. 2008;60:1–18.
- Banlaki Z, Doleschall M, Rajczy K, Fust G, Szilagyi A. Fine-tuned characterization of RCCX copy number variants and their relationship with extended MHC haplotypes. Genes Immun. 2012;13:530–535.
- Law SK, Dodds AW, Porter RR. A comparison of the properties of two classes, C4A and C4B, of the human complement component C4. EMBO J. 1984;3:1819–1823.
- Isenman DE, Young JR. The molecular basis for the difference in immune hemolysis activity of the Chido and Rodgers isotypes of human complement component C4. J Immunol. 1984;132:3019–3027.
- Illarionova AE, Vinogradova TV, Sverdlov ED. Only those genes of the KIAA1245 gene subfamily that contain HERV(K) LTRs in their introns are transcriptionally active. Virology. 2007;358:39–47.
- Nakamura A, Okazaki Y, Sugimoto J, Oda T, Jinno Y. Human endogenous retroviruses with transcriptional potential in the brain. Journal of human genetics. 2003;48:575–581.
- Suntsova M, et al. Human-specific endogenous retroviral insert serves as an enhancer for the schizophrenia-linked gene PRODH. Proceedings of the National Academy of Sciences of the United States of America. 2013;110:19472–19477.
- Yang Y, et al. 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. J Immunol. 2003;171:2734–2745.
- Browning SR, Browning BL. Rapid and accurate haplotype phasing and missing-data inference for whole-genome association studies by use of localized haplotype clustering. Am J Hum Genet. 2007;81:1084–1097.
- Iossifov I, et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature. 2014;515:216–221.
- Mayilyan KR, Arnold JN, Presanis JS, Soghoyan AF, Sim RB. Increased complement classical and mannan-binding lectin pathway activities in schizophrenia. Neurosci Lett. 2006;404:336–341.
- Hakobyan S, Boyajyan A, Sim RB. Classical pathway complement activity in schizophrenia. Neurosci Lett. 2005;374:35–37.
- Stevens B, et al. The classical complement cascade mediates CNS synapse elimination. Cell. 2007;131:1164–1178.
- Schafer DP, et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron. 2012;74:691–705.
- Bialas AR, Stevens B. TGF-beta signaling regulates neuronal C1q expression and developmental synaptic refinement. Nat Neurosci. 2013;16:1773–1782.
- Kaiser T, Feng G. Modeling psychiatric disorders for developing effective treatments. Nat Med. 2015;21:979–988.
- Shatz CJ, Kirkwood PA. Prenatal development of functional connections in the cat's retinogeniculate pathway. J Neurosci. 1984;4:1378–1397.
- Sretavan DW, Shatz CJ. Prenatal development of retinal ganglion cell axons: segregation into eye-specific layers within the cat's lateral geniculate nucleus. J Neurosci. 1986;6:234–251.
- Chen C, Regehr WG. Developmental remodeling of the retinogeniculate synapse. Neuron. 2000;28:955–966.
- Fischer MB, et al. Regulation of the B cell response to T-dependent antigens by classical pathway complement. J Immunol. 1996;157:549–556.
- Huttenlocher PR, Dabholkar AS. Regional differences in synaptogenesis in human cerebral cortex. J Comp Neurol. 1997;387:167–178.
- Huttenlocher PR. Synaptic density in human frontal cortex - developmental changes and effects of aging. Brain Res. 1979;163:195–205.
- Petanjek Z, et al. Extraordinary neoteny of synaptic spines in the human prefrontal cortex. Proceedings of the National Academy of Sciences of the United States of America. 2011;108:13281–13286.
- Buckner RL, Krienen FM. The evolution of distributed association networks in the human brain. Trends Cogn Sci. 2013;17:648–665.
- Feinberg I. Schizophrenia: caused by a fault in programmed synaptic elimination during adolescence? Journal of psychiatric research. 1982;17:319–334.
- Kirov G, et al. De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia. Mol Psychiatry. 2012;17:142–153.
- Fromer M, et al. De novo mutations in schizophrenia implicate synaptic networks. Nature. 2014;506:179–184.
- Purcell SM, et al. A polygenic burden of rare disruptive mutations in schizophrenia. Nature. 2014;506:185–190.
- Datwani A, et al. Classical MHCI molecules regulate retinogeniculate refinement and limit ocular dominance plasticity. Neuron. 2009;64:463–470.
- Lee H, et al. Synapse elimination and learning rules co-regulated by MHC class I H2-Db. Nature. 2014;509:195–200.
- van den Elsen JM, et al. X-ray crystal structure of the C4d fragment of human complement component C4. J Mol Biol. 2002;322:1103–1115.
- Dodds AW, Ren XD, Willis AC, Law SK. The reaction mechanism of the internal thioester in the human complement component C4. Nature. 1996;379:177–179.
- Handsaker RE, et al. Large multiallelic copy number variations in humans. Nature genetics. 2015;47:296–303.
- Torborg CL, Feller MB. Unbiased analysis of bulk axonal segregation patterns. J Neurosci Methods. 2004;135:17–26.
- Fernando MM, et al. Assessment of complement C4 gene copy number using the paralog ratio test. Hum Mutat. 2010;31:866–874.
- Rudduck C, Beckman L, Franzen G, Jacobsson L, Lindstrom L. Complement factor C4 in schizophrenia. Hum Hered. 1985;35:223–226.
- Schroers R, et al. Investigation of complement C4B deficiency in schizophrenia. Hum Hered. 1997;47:279–282.
- Mayilyan KR, Dodds AW, Boyajyan AS, Soghoyan AF, Sim RB. Complement C4B protein in schizophrenia. World J Biol Psychiatry. 2008;9:225–230.
- Jia X, et al. Imputing amino acid polymorphisms in human leukocyte antigens. PLoS One. 2013;8:e64683.
- Nonaka M, Nakayama K, Yeul YD, Takahashi M. Complete nucleotide and derived amino acid sequences of sex-limited protein (Slp), nonfunctional isotype of the fourth component of mouse complement (C4) J Immunol. 1986;136:2989–2993.
Source: PubMed