Summary statistics from a genome-wide association study of narcolepsy

Type 1 narcolepsy (T1N) is a neurological condition, in which the death of hypocretin-producing neurons in the lateral hypothalamus leads to excessive daytime sleepiness and symptoms of abnormal Rapid Eye Movement (REM) sleep. Known triggers for narcolepsy are influenza-A infection and associated immunization during the 2009 H1N1 influenza pandemic. Here, we genotyped all remaining consented narcolepsy cases worldwide and assembled this with the existing genotyped individuals. We used this multi-ethnic sample in genome wide association study (GWAS) to dissect disease mechanisms and interactions with environmental triggers (5,339 cases and 20,518 controls). Overall, we found significant associations with HLA (2 GWA significant subloci) and 11 other loci. Six of these other loci have been previously reported (TRA, TRB, CTSH, IFNAR1, ZNF365 and P2RY11) and five are new (PRF1, CD207, SIRPG, IL27 and ZFAND2A). Strikingly, in vaccination-related cases, GWA significant effects were found in HLA, TRA, and in a novel variant near SIRPB1. Furthermore, IFNAR1-associated polymorphisms regulated dendritic cell response to influenza-A infection in vitro (p-value =1.92*10-25). A partitioned heritability analysis indicated specific enrichment of functional elements active in cytotoxic and helper T cells. Furthermore, functional analysis showed the genetic variants in TRA and TRB loci act as remarkably strong chain usage QTLs for TRAJ*24 (p-value = 0.0017), TRAJ*28 (p-value = 1.36*10-10) and TRBV*4-2 (p-value = 3.71*10-117). This was further validated in TCR sequencing of 60 narcolepsy cases and 60 DQB1*06:02 positive controls, where chain usage effects were further accentuated. Together these findings show that the autoimmune component in narcolepsy is defined by antigen presentation, mediated through specific T cell receptor chains, and modulated by influenza-A as a critical trigger.

1型发作性睡病（Type 1 narcolepsy, T1N）是一种神经系统疾病，其病因是外侧下丘脑内产生食欲素的神经元死亡，进而导致日间过度嗜睡及异常快速眼动（REM）睡眠相关症状。已知发作性睡病的触发因素包括2009年甲型H1N1流感大流行期间的甲型流感病毒感染及相关免疫接种。本研究对全球范围内所有签署知情同意的发作性睡病病例进行了全基因分型，并将其与已完成基因分型的个体数据整合。我们利用该多族裔样本开展全基因组关联研究（GWAS），以解析疾病发生机制及与环境触发因素的相互作用（共纳入5339例病例与20518例对照）。总体而言，我们发现人类白细胞抗原（HLA，包含2个全基因组关联显著亚位点）及另外11个基因位点与疾病存在显著关联。其中6个位点此前已有报道（TRA、TRB、CTSH、IFNAR1、ZNF365及P2RY11），剩余5个为新发现位点（PRF1、CD207、SIRPG、IL27及ZFAND2A）。值得注意的是，在疫苗接种相关病例中，我们在HLA、TRA及SIRPB1附近的新型变异位点中发现了全基因组关联显著效应。此外，IFNAR1相关多态性可在体外调控树突状细胞对甲型流感病毒感染的应答（p值=1.92×10^-25）。分层遗传力分析显示，细胞毒性T细胞与辅助性T细胞中活跃的功能元件存在特异性富集。进一步功能分析表明，TRA与TRB位点的遗传变异可作为极强的链使用数量性状基因座（QTL），分别调控TRAJ*24（p值=0.0017）、TRAJ*28（p值=1.36×10^-10）及TRBV*4-2（p值=3.71×10^-117）的基因表达。该结果在60例发作性睡病病例与60例HLA-DQB1*06:02阳性对照的T细胞受体（TCR）测序中得到了进一步验证，且链使用效应更为显著。综上，本研究结果表明，发作性睡病的自身免疫组分由抗原呈递过程所定义，该过程通过特定T细胞受体链介导，并受甲型流感病毒作为关键触发因素调控。