Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix®. Here, we dissect... Show moreNarcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix®. Here, we dissect disease mechanisms and interactions with environmental triggers in a multi-ethnic sample of 6,073 cases and 84,856 controls. We fine-mapped GWAS signals within HLA (DQ0602, DQB1*03:01 and DPB1*04:02) and discovered seven novel associations (CD207, NAB1, IKZF4-ERBB3, CTSC, DENND1B, SIRPG, PRF1). Significant signals at TRA and DQB1*06:02 loci were found in 245 vaccination-related cases, who also shared polygenic risk. T cell receptor associations in NT1 modulated TRAJ*24, TRAJ*28 and TRBV*4-2 chain-usage. Partitioned heritability and immune cell enrichment analyses found genetic signals to be driven by dendritic and helper T cells. Lastly comorbidity analysis using data from FinnGen, suggests shared effects between NT1 and other autoimmune diseases. NT1 genetic variants shape autoimmunity and response to environmental triggers, including influenza A infection and immunization with Pandemrix®. Show less
The classification of the central disorders of hypersomnolence has undergone multiple iterations in an attempt to capture biologically meaningful disease entities in the absence of known... Show moreThe classification of the central disorders of hypersomnolence has undergone multiple iterations in an attempt to capture biologically meaningful disease entities in the absence of known pathophysiology. Accumulating data suggests that further refinements may be necessary. At the 7th International Symposium on Narcolepsy, a group of clinician-scientists evaluated data in support of keeping or changing classifications, and as a result suggest several changes. First, idiopathic hypersomnia with long sleep durations appears to be an identifiable and meaningful disease subtype. Second, idiopathic hypersomnia without long sleep time and narcolepsy without cataplexy share substantial phenotypic overlap and cannot reliably be distinguished with current testing, and so combining them into a single disease entity seems warranted at present. Moving forward, it is critical to phenotype patients across a wide variety of clinical and biological features, to aid in future refinements of disease classification. Show less
Heide, A. van der; Schie, M.K.M. van; Lammers, G.J.; Dauvilliers, Y.; Arnulf, I.; Mayer, G.; ... ; Dijk, J.G. van 2015
Narcolepsy is a rare sleep disorder with the strongest human leukocyte antigen (HLA) association ever reported. Since the associated HLA-DRB1*1501-DQB1*0602 haplotype is common in the general... Show moreNarcolepsy is a rare sleep disorder with the strongest human leukocyte antigen (HLA) association ever reported. Since the associated HLA-DRB1*1501-DQB1*0602 haplotype is common in the general population (15-25%), it has been suggested that it is almost necessary but not sufficient for developing narcolepsy. To further define the genetic basis of narcolepsy risk, we performed a genome-wide association study (GWAS) in 562 European individuals with narcolepsy (cases) and 702 ethnically matched controls, with independent replication in 370 cases and 495 controls, all heterozygous for DRB1*1501-DQB1*0602. We found association with a protective variant near HLA-DQA2 (rs2858884; P < 3 x 10(-8)). Further analysis revealed that rs2858884 is strongly linked to DRB1*03DQB1*02 (P < 4 x 10(-43)) and DRB1*1301-DQB1*0603 (P < 3 x 10(-7)). Cases almost never carried a trans DRB1*1301-DQB1*0603 haplotype (odds ratio = 0.02; P < 6 x 10(-14)). This unexpected protective HLA haplotype suggests a virtually causal involvement of the HLA region in narcolepsy susceptibility. Show less
