Journal
NATURE GENETICS
Volume 43, Issue 1, Pages 66-U90Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.734
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Funding
- National Institutes of neurological Disease [P50 NS2372]
- Danish Medical Council [09-066348/FSS, 5 T32 AI07290]
- National Institutes of Mental Health [R01 MH080957, 5U01 MH079470]
- US National Institutes of Health [NS-044199]
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [T32AI007290] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF MENTAL HEALTH [U01MH079470, R01MH080957] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [P50NS023724, R01NS044199] Funding Source: NIH RePORTER
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Growing evidence supports the hypothesis that narcolepsy with cataplexy is an autoimmune disease. We here report genome-wide association analyses for narcolepsy with replication and fine mapping across three ethnic groups (3,406 individuals of European ancestry, 2,414 Asians and 302 African Americans). We identify a SNP in the 3' untranslated region of P2RY11, the purinergic receptor subtype P2Y(11) gene, which is associated with narcolepsy (rs2305795, combined P = 6.1 x 10(-10), odds ratio = 1.28, 95% CI 1.19-1.39, n = 5689). The disease-associated allele is correlated with reduced expression of P2RY11 in CD8(+) T lymphocytes (339% reduced, P = 0.003) and natural killer (NK) cells (P = 0.031), but not in other peripheral blood mononuclear cell types. The low expression variant is also associated with reduced P2RY11-mediated resistance to ATP-induced cell death in T lymphocytes (P = 0.0007) and natural killer cells (P = 0.001). These results identify P2RY11 as an important regulator of immune-cell survival, with possible implications in narcolepsy and other autoimmune diseases.
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