EIF3G is associated with narcolepsy across ethnicities

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Anja Holm, Ling Lin, Juliette Faraco, Sara Mostafavi, Alexis Battle, Xiaowei Zhu, Douglas F Levinson, Fang Han, Steen Gammeltoft, Poul Jennum, Emmanuel Mignot, Birgitte R Kornum

Type 1 narcolepsy, an autoimmune disease affecting hypocretin (orexin) neurons, is strongly associated with HLA-DQB1*06:02. Among polymorphisms associated with the disease is single-nucleotide polymorphism rs2305795 (c.*638G>A) located within the P2RY11 gene. P2RY11 is in a region of synteny conserved in mammals and zebrafish containing PPAN, EIF3G and DNMT1 (DNA methyltransferase 1). As mutations in DNMT1 cause a rare dominant form of narcolepsy in association with deafness, cerebellar ataxia and dementia, we questioned whether the association with P2RY11 in sporadic narcolepsy could be secondary to linkage disequilibrium with DNMT1. Based on genome-wide association data from two cohorts of European and Chinese ancestry, we found that the narcolepsy association signal drops sharply between P2RY11/EIF3G and DNMT1, suggesting that the association with narcolepsy does not extend into the DNMT1 gene region. Interestingly, using transethnic mapping, we identified a novel single-nucleotide polymorphism rs3826784 (c.596-260A>G) in the EIF3G gene also associated with narcolepsy. The disease-associated allele increases EIF3G mRNA expression. EIF3G is located in the narcolepsy risk locus and EIF3G expression correlates with PPAN and P2RY11 expression. This suggests shared regulatory mechanisms that might be affected by the polymorphism and are of relevance to narcolepsy.

Original languageEnglish
JournalEuropean Journal of Human Genetics
Volume23
Issue number11
Pages (from-to)1573-80
Number of pages8
ISSN1018-4813
DOIs
Publication statusPublished - 2015

    Research areas

  • Alleles, Animals, DNA (Cytosine-5-)-Methyltransferase, Ethnic Groups, Eukaryotic Initiation Factor-3, Female, Gene Expression Regulation, Genetic Predisposition to Disease, Genome-Wide Association Study, HLA-DQ beta-Chains, Humans, Male, Mutation, Narcolepsy, Nuclear Proteins, Polymorphism, Single Nucleotide, Receptors, Purinergic P2

ID: 162693918