Narcolepsy-cataplexy is a serious and chronic sleep disorder resulting in excessive daytime sleepiness and cataplexy. It is one of the most common neurological disorders, affecting approximately 1 in 2,000 individuals in North America. The disease often develops during childhood, resulting in dramatic challenges at school, at work, and at home, and has devastating effects on physical, mental, and social health. Recent discoveries have provided firm evidence that narcolepsy/hypocretin deficiency is an autoimmune disorder affecting the brain, and more particularly hypocretin-expressing neurons, with resulting hypocretin loss causing sleep disturbances. A crucial susceptibility factor is HLA-DQB1*0602, but family and twin studies support the function of additional genetic factors, as seen in other autoimmune disorders. Recently two such susceptibility genes have been identified through a genome wide association study (GWAS) design: the T cell receptor alpha gene (TCRA) and a purinergic receptor, P2RY11. It is now crucial to identify the specific mutations underlying narcolepsy at these two loci. We will therefore comprehensively sequence these two genomic regions in 1400 narcolepsy subjects (to be compared to a large number of publicly available control DNA sequences) and identify the sequence variants underlying this genetic association, also possibly identifying rare variants with potentially larger effects on susceptibility. Variants that are associated with narcolepsy will be replicated in a total of 2000 narcolepsy cases and 2000 controls. Other large-scale GWAS have demonstrated that autoimmune diseases share common susceptibility loci. As sufficient numbers of susceptibility loci are identified, overlapping patterns of association point to immune pathways underlying disease pathophysiologies. We will therefore double the sample size of our first GWAS (to 1600 narcolepsy versus a large number of controls), which will increase our power to detect novel susceptibility loci acting in narcolepsy. Findings from this expanded GWA will be tested for replication in a total of 2000 cases and 2000 controls, and replicated loci will be followed up through comprehensive sequencing. Using genetics to understand the highly specific immunological pathology in narcolepsy will also be insightful for more common and complex autoimmune diseases and potentially uncover yet unknown neurological disorders with similar autoimmune basis.

Public Health Relevance

Narcolepsy-cataplexy is a serious and chronic sleep disorder resulting in excessive daytime sleepiness and cataplexy. It is one of the most common neurological disorders, affecting approximately 1 in 2,000 individuals in North America. Our research aims to understand the genetics of this disorder thus allowing for the development of better treatment (s) for this condifion.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Specialized Center (P50)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Stanford University
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Bonvalet, Melodie; Ollila, Hanna M; Ambati, Aditya et al. (2017) Autoimmunity in narcolepsy. Curr Opin Pulm Med 23:522-529
Plante, David T; Finn, Laurel A; Hagen, Erika W et al. (2016) Subjective and Objective Measures of Hypersomnolence Demonstrate Divergent Associations with Depression among Participants in the Wisconsin Sleep Cohort Study. J Clin Sleep Med 12:571-8
Gottlieb, D J; Hek, K; Chen, T-H et al. (2015) Novel loci associated with usual sleep duration: the CHARGE Consortium Genome-Wide Association Study. Mol Psychiatry 20:1232-9
Ollila, Hanna M; Ravel, Jean-Marie; Han, Fang et al. (2015) HLA-DPB1 and HLA class I confer risk of and protection from narcolepsy. Am J Hum Genet 96:136-46
Li, Jason; Moore 4th, Hyatt; Lin, Ling et al. (2015) Association of low ferritin with PLM in the Wisconsin Sleep Cohort. Sleep Med 16:1413-1418
Kornum, Birgitte Rahbek; Pizza, Fabio; Knudsen, Stine et al. (2015) Cerebrospinal fluid cytokine levels in type 1 narcolepsy patients very close to onset. Brain Behav Immun 49:54-8
Holm, Anja; Lin, Ling; Faraco, Juliette et al. (2015) EIF3G is associated with narcolepsy across ethnicities. Eur J Hum Genet 23:1573-80
Kawai, Makoto; O'Hara, Ruth; Einen, Mali et al. (2015) Narcolepsy in African Americans. Sleep 38:1673-81
Jacob, Louis; Leib, Ryan; Ollila, Hanna M et al. (2015) Comparison of Pandemrix and Arepanrix, two pH1N1 AS03-adjuvanted vaccines differentially associated with narcolepsy development. Brain Behav Immun 47:44-57
de Lecea, Luis (2015) Optogenetic control of hypocretin (orexin) neurons and arousal circuits. Curr Top Behav Neurosci 25:367-78

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