Genetics of Human Narcolepsy

发作性睡病是一种严重的慢性睡眠障碍，导致白天过度嗜睡和昏厥。它是最常见的神经系统疾病之一，在北美大约每2,000人中就有1人受到影响。这种疾病通常在儿童时期发展，导致学校，工作和家庭的巨大挑战，并对身体，心理和社会健康产生破坏性影响。 最近的发现提供了有力的证据，即发作性睡病/下丘脑泌素缺乏症是影响大脑的自身免疫性疾病，更具体地说是影响下丘脑泌素表达神经元的自身免疫性疾病，所导致的下丘脑泌素损失引起睡眠障碍。一个关键的易感因素是HLA-DQB 1 *0602，但家族和双胞胎研究支持其他遗传因素的功能，如在其他自身免疫性疾病中所见。最近，通过全基因组关联研究（GWAS）设计已经鉴定了两个这样的易感基因：T细胞受体α基因（TCRA）和嘌呤能受体P2 RY 11。现在关键是要确定在这两个位点的嗜睡症的具体突变。因此，我们将对1400名发作性睡病受试者的这两个基因组区域进行全面测序（与大量公开可用的对照DNA序列进行比较），并确定这种遗传关联背后的序列变异，还可能确定对易感性具有潜在较大影响的罕见变异。将在总共2000例发作性睡病病例和2000例对照中复制与发作性睡病相关的变体。 其他大规模的GWAS已经证明，自身免疫性疾病具有共同的易感基因座。当鉴定出足够数量的易感基因座时，重叠的关联模式指向疾病病理生理学基础的免疫途径。因此，我们将把我们第一个GWAS的样本量增加一倍（1600例发作性睡病与大量对照），这将增加我们检测发作性睡病中新易感基因座的能力。将在总共2000例病例和2000例对照中对来自这一扩大的GWA的发现进行复制测试，并将通过全面测序对复制的位点进行随访。利用遗传学来了解嗜睡症中高度特异性的免疫病理学也将对更常见和复杂的自身免疫性疾病具有深刻的见解，并可能发现具有类似自身免疫性基础的未知神经系统疾病。

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.