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Schizophrenia risk from complex variation of complement component 4

Author

Listed:
  • Aswin Sekar

    (Harvard Medical School
    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
    MD-PhD Program, Harvard Medical School)

  • Allison R. Bialas

    (F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School
    Program in Cellular and Molecular Medicine, Boston Children’s Hospital)

  • Heather de Rivera

    (Harvard Medical School
    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard)

  • Avery Davis

    (Harvard Medical School
    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard)

  • Timothy R. Hammond

    (F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School)

  • Nolan Kamitaki

    (Harvard Medical School
    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard)

  • Katherine Tooley

    (Harvard Medical School
    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard)

  • Jessy Presumey

    (Program in Cellular and Molecular Medicine, Boston Children’s Hospital)

  • Matthew Baum

    (Harvard Medical School
    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
    MD-PhD Program, Harvard Medical School
    F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School)

  • Vanessa Van Doren

    (Harvard Medical School)

  • Giulio Genovese

    (Harvard Medical School
    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard)

  • Samuel A. Rose

    (Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard)

  • Robert E. Handsaker

    (Harvard Medical School
    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard)

  • Mark J. Daly

    (Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
    Analytical and Translational Genetics Unit, Massachusetts General Hospital)

  • Michael C. Carroll

    (Program in Cellular and Molecular Medicine, Boston Children’s Hospital)

  • Beth Stevens

    (Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
    F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School)

  • Steven A. McCarroll

    (Harvard Medical School
    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard)

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.

Suggested Citation

  • 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 & Samue, 2016. "Schizophrenia risk from complex variation of complement component 4," Nature, Nature, vol. 530(7589), pages 177-183, February.
    • Handle: RePEc:nat:nature:v:530:y:2016:i:7589:d:10.1038_nature16549
    DOI: 10.1038/nature16549
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    Cited by:

    1. Gianluca Ursini & Pasquale Di Carlo & Sreya Mukherjee & Qiang Chen & Shizhong Han & Jiyoung Kim & Maya Deyssenroth & Carmen J. Marsit & Jia Chen & Ke Hao & Giovanna Punzi & Daniel R. Weinberger, 2023. "Prioritization of potential causative genes for schizophrenia in placenta," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Jessica Gracias & Funda Orhan & Elin Hörbeck & Jessica Holmén-Larsson & Neda Khanlarkani & Susmita Malwade & Sravan K. Goparaju & Lilly Schwieler & İlknur Ş. Demirel & Ting Fu & Helena Fatourus-Bergma, 2022. "Cerebrospinal fluid concentration of complement component 4A is increased in first episode schizophrenia," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    3. Taotao Li & Duo Du & Dandan Zhang & Yicheng Lin & Jiakang Ma & Mengyu Zhou & Weida Meng & Zelin Jin & Ziqiang Chen & Haozhe Yuan & Jue Wang & Shulong Dong & Shaoyang Sun & Wenjing Ye & Bosen Li & Houb, 2023. "CRISPR-based targeted haplotype-resolved assembly of a megabase region," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    4. Ya-Qiang Zhang & Wei-Peng Lin & Li-Ping Huang & Bing Zhao & Cheng-Cheng Zhang & Dong-Min Yin, 2021. "Dopamine D2 receptor regulates cortical synaptic pruning in rodents," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    5. Kellianne D. Alexander & Shankar Ramachandran & Kasturi Biswas & Christopher M. Lambert & Julia Russell & Devyn B. Oliver & William Armstrong & Monika Rettler & Samuel Liu & Maria Doitsidou & Claire B, 2023. "The homeodomain transcriptional regulator DVE-1 directs a program for synapse elimination during circuit remodeling," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    6. Ilenia Lovato & Alessia Pini & Aymeric Stamm & Maxime Taquet & Simone Vantini, 2021. "Multiscale null hypothesis testing for network‐valued data: Analysis of brain networks of patients with autism," Journal of the Royal Statistical Society Series C, Royal Statistical Society, vol. 70(2), pages 372-397, March.
    7. Mary-Ellen Lynall & Blagoje Soskic & James Hayhurst & Jeremy Schwartzentruber & Daniel F. Levey & Gita A. Pathak & Renato Polimanti & Joel Gelernter & Murray B. Stein & Gosia Trynka & Menna R. Clatwor, 2022. "Genetic variants associated with psychiatric disorders are enriched at epigenetically active sites in lymphoid cells," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    8. Aleksandr Talishinsky & Jonathan Downar & Petra E. Vértes & Jakob Seidlitz & Katharine Dunlop & Charles J. Lynch & Heather Whalley & Andrew McIntosh & Fidel Vila-Rodriguez & Zafiris J. Daskalakis & Da, 2022. "Regional gene expression signatures are associated with sex-specific functional connectivity changes in depression," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    9. Kurt Farrell & Jack Humphrey & Timothy Chang & Yi Zhao & Yuk Yee Leung & Pavel P. Kuksa & Vishakha Patil & Wan-Ping Lee & Amanda B. Kuzma & Otto Valladares & Laura B. Cantwell & Hui Wang & Ashvin Ravi, 2024. "Genetic, transcriptomic, histological, and biochemical analysis of progressive supranuclear palsy implicates glial activation and novel risk genes," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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