EIF3G is associated with narcolepsy across ethnicities

TY - JOUR

T1 - EIF3G is associated with narcolepsy across ethnicities

AU - Holm, Anja

AU - Lin, Ling

AU - Faraco, Juliette

AU - Mostafavi, Sara

AU - Battle, Alexis

AU - Zhu, Xiaowei

AU - Levinson, Douglas F

AU - Han, Fang

AU - Gammeltoft, Steen

AU - Jennum, Poul

AU - Mignot, Emmanuel

AU - Kornum, Birgitte R

PY - 2015/10/1

Y1 - 2015/10/1

N2 - 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.

AB - 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.

KW - Alleles

KW - Animals

KW - DNA (Cytosine-5-)-Methyltransferase

KW - Ethnic Groups

KW - Eukaryotic Initiation Factor-3

KW - Female

KW - Gene Expression Regulation

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - HLA-DQ beta-Chains

KW - Humans

KW - Male

KW - Mutation

KW - Narcolepsy

KW - Nuclear Proteins

KW - Polymorphism, Single Nucleotide

KW - Receptors, Purinergic P2

U2 - 10.1038/ejhg.2015.4

DO - 10.1038/ejhg.2015.4

M3 - Journal article

C2 - 25669430

SN - 1018-4813

VL - 23

SP - 1573

EP - 1580

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

IS - 11

ER -