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.*638G4A) 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.596-260A4G) 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. INTRODUCTIONNarcolepsy with cataplexy (Type 1 narcolepsy) affects 1 in 3000 individuals and is caused by the loss of around 70 000 hypocretin-(hcrt, also known as orexin) producing neurons in the hypothalamus. The disease is strongly associated with HLA-DQB1*06:02 and DQA1*01:02, 1 the T-cell receptor alpha locus 2 and polymorphisms in other immune-related genes. 3 The loss of hcrt-producing cells is hypothesized to have an autoimmune basis. 4 One of the genetic associations in narcolepsy is rs2305795, a polymorphism located in the purinergic receptor P2RY11. 5,6 The disease-associated allele of rs2305795 decreases P2RY11 expression and increases the sensitivity of CD8 + T cells to cell death induced by ATP. Interestingly, we also recently found that missense mutation in exon 21 of the DNA methyltransferase 1 (DNMT1) gene causes a rare hereditary form of narcolepsy-associated deafness, cerebellar ataxia and eventually dementia (ADCA-DN). 7 As the P2RY11 and DNMT1 genes are located in close proximity (within 18 kb) on chromosome 19, we hypothesized that the two signals could be related at the pathophysiological level. In support of this hypothesis, Kornum et al. 5 observed a correlation between P2RY11 and DNMT1 expression in peripheral blood mononuclear cells (PBMCs) of both patients and healthy controls. These findings made us question whether the association with P2RY11 in spontaneous narcolepsy could be secondary to linkage disequilibrium (LD) with DNMT1. In the original study, Kornum et al. 5 fine-mapped the locus using seven single-nucleotide polymorphisms (SNPs) and reported an association between DNMT1 and narcolepsy in individuals of European anc...

Pleiotropic genetic effects influencing sleep and neurological disorders

“…The most significant associations were located in a PPAN-P2RY11-EIF3G haplotype block, not in DNMT1. 84 The most consistent association was for a eukaryotic translation initiation factor 3 subunit G (EIF3G) variant that increased EIF3G expression, which correlated with P2RY11 expression. 84 Thus, variants in EIF3G might regulate expression of P2RY11, and effects of regional variation on narcolepsy might relate to dysregulation of multiple genes.…”

Genetic Ancestry for Sleep Research

“…Beyond the HLA genes, other risk genes have also been implicated in the development of narcolepsy in various racial/ethnic groups (Table 3). Associations between narcolepsy and polymorphisms in the TCRA locus 81 , in the P2RY11 gene 82 , and in the EIF3G gene 83 have been found in AAs and EAs.…”

A critical look at the function of the P2Y11 receptor

“…Another P2RY11 polymorphism (rs2305795) is associated with the sleep disorder narcolepsy [18,127]. It is unclear whether this has a functional effect on the pathogenesis or is merely the result of linkage disequilibrium between another associated polymorphism located in the neighboring gene, EIF3G (rs3826784) [128]. The P2RY11 rs2305795 polymorphism is located in the 3′-untranslated region that usually plays a role in regulating transcription.…”