title: EIF3G is associated with narcolepsy across ethnicities.
abstract: 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.
authors: Molecular Sleep Laboratory, Department of Diagnostics, Glostrup University Hospital, Glostrup, Denmark.|Danish Center for Sleep Medicine, Department of Neurophysiology, Glostrup Hospital, University of Copenhagen, Glostrup, Denmark.
authors: Anja
authors: A
authors: Holm
authors: Center for Sleep Sciences in Medicine and Department of Psychiatry, Stanford University School of Medicine, Palo Alto, CA, USA.
authors: Ling
authors: L
authors: Lin
authors: Center for Sleep Sciences in Medicine and Department of Psychiatry, Stanford University School of Medicine, Palo Alto, CA, USA.
authors: Juliette
authors: J
authors: Faraco
authors: Department of Computer Science, Stanford University, Palo Alto, CA, USA.
authors: Sara
authors: S
authors: Mostafavi
authors: Department of Computer Science, Stanford University, Palo Alto, CA, USA.
authors: Alexis
authors: A
authors: Battle
authors: Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, CA, USA.
authors: Xiaowei
authors: X
authors: Zhu
authors: Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, CA, USA.
authors: Douglas F
authors: DF
authors: Levinson
authors: Department of Pulmonary, Critical Care Medicine, Peking University People's Hospital, Beijing, China.
authors: Fang
authors: F
authors: Han
authors: Molecular Sleep Laboratory, Department of Diagnostics, Glostrup University Hospital, Glostrup, Denmark.
authors: Steen
authors: S
authors: Gammeltoft
authors: Danish Center for Sleep Medicine, Department of Neurophysiology, Glostrup Hospital, University of Copenhagen, Glostrup, Denmark.
authors: Poul
authors: P
authors: Jennum
authors: Center for Sleep Sciences in Medicine and Department of Psychiatry, Stanford University School of Medicine, Palo Alto, CA, USA.
authors: Emmanuel
authors: E
authors: Mignot
authors: Molecular Sleep Laboratory, Department of Diagnostics, Glostrup University Hospital, Glostrup, Denmark.
authors: Birgitte R
authors: BR
authors: Kornum
mesh_terms: D000483:Alleles; D000818:Animals; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D005006:Ethnicity / Q000235:genetics; D039621:Eukaryotic Initiation Factor-3 / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D059866:HLA-DQ beta-Chains / Q000235:genetics; D006801:Humans; D008297:Male; D009154:Mutation; D009290:Narcolepsy / Q000235:genetics* / Q000473:pathology; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D018048:Receptors, Purinergic P2 / Q000096:biosynthesis / Q000235:genetics
chemical_list: D039621:Eukaryotic Initiation Factor-3; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D009687:Nuclear Proteins; C109734:P2RY11 protein, human; C491917:PPAN protein, human; D018048:Receptors, Purinergic P2; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human