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0002 FINE MAPPING GENOME-WIDE ASSOCIATION IN NARCOLEPSY DEFINES NOVEL DISEASE MECHANISMS

Sleep (New York, N.Y.), 2017-04, Vol.40 (suppl_1), p.A1-A1 [Peer Reviewed Journal]

Sleep Research Society 2017. Published by Oxford University Press [on behalf of the Sleep Research Society]. All rights reserved. For permissions, please email: journals.permissions@oup.com 2017 ;Sleep Research Society 2017. Published by Oxford University Press [on behalf of the Sleep Research Society]. All rights reserved. For permissions, please email: journals.permissions@oup.com ;ISSN: 0161-8105 ;EISSN: 1550-9109 ;DOI: 10.1093/sleepj/zsx050.001

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  • Title:
    0002 FINE MAPPING GENOME-WIDE ASSOCIATION IN NARCOLEPSY DEFINES NOVEL DISEASE MECHANISMS
  • Author: Ollila, HM ; Hillary, R ; Lin, L ; Hallmayer, J ; Han, F ; Ye, J ; Mignot, E
  • Subjects: Consortia ; Dendritic cells ; Lymphocytes ; Sleep disorders
  • Is Part Of: Sleep (New York, N.Y.), 2017-04, Vol.40 (suppl_1), p.A1-A1
  • Description: Abstract Introduction: Type 1 narcolepsy is characterized by sleepiness, REM sleep abnormalities and loss of muscle tone triggered by positive emotions (cataplexy). The cause of type 1 narcolepsy is a loss of neurons producing the hypocretin/orexin peptide likely of autoimmune origin. Our aim was to discover novel genetic variants in narcolepsy and fine map the potentially causative variants using our transethnic sample and cellular models. Methods: A worldwide narcolepsy collaboration was built over the last two decades. Within this consortium, we examined genetic variants using a transethnic GWAS in Asian, African American and Caucasian samples (N=5,500 cases and 30,000 controls). The function of leading variants was examined using eQTL analysis in dendritic and T cell models, data from the ENCODE and GTEx consortiums and by examining the effect of individual variants on flu vaccination response. In addition the effect of genetic variants on immune cell development was examined using mass cytometry. Results: We confirmed existing risk associations (TRA, TRB, IFNAR1, CTSH and P2RY11) and discovered novel loci that predisposed individuals to narcolepsy in CD207, SIRPG, PPP2R2C, ZFAND2A, FLT3, LPP and PRF1. Fine mapping of association suggests a functional polymorphism in position A91V in PRF1, a variant that is directly affecting T and NK cell mediated cell killing. Furthermore, leading variant in IFNAR1 affected IFNAR1 expression after flu infection in dendritic cells suggesting causality for the development of narcolepsy through changes in dendritic cell phenotype. Conclusion: The results further stress the effect of T cell-dendritic cell interactions in the development of narcolepsy and find causal disease pathways. The novel loci may explain how hypocretin cells are destroyed and support a T cell mediated autoimmune attack in narcolepsy susceptibility. Support (If Any): World Wide Narcolepsy Consortium, European Narcolepsy Network, Sigrid Juselius Foundation, Finnish Cultural Foundation.
  • Publisher: US: Oxford University Press
  • Language: English
  • Identifier: ISSN: 0161-8105
    EISSN: 1550-9109
    DOI: 10.1093/sleepj/zsx050.001
  • Source: ProQuest One Psychology
    AUTh Library subscriptions: ProQuest Central
    Alma/SFX Local Collection
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