Kleine-Levin Syndrome (KLS) is a rare disorder characterized by severe episodic hypersomnia, with cognitive impairment accompanied by apathy or disinhibition. Pathophysiology is unknown, although imaging studies indicate decreased activity in hypothalamic/thalamic areas during episodes. Familial occurrence is increased, and risk is associated with reports of a difficult birth. We conducted a worldwide case-control genome wide association study in 673 KLS cases collected over 14 years, and ethnically matched 15,341 control individuals. We found a strong genome-wide significant association (OR=1.48,rs71947865,p=8.6x10-9) with 20 single nucleotide polymorphisms encompassing a 35kb region located in the 3[prime] region of TRANK1 gene, previously associated with bipolar disorder and schizophrenia. Strikingly, KLS cases with TRANK1 rs71947865 variant had significantly increased reports of a difficult birth. As perinatal outcomes have dramatically improved over the last 40 years, we further stratified our sample by birth years and found that recent cases had a significantly reduced TRANK1 rs71947865 association. While the TRANK1 rs71947865 association did not replicate in the entire follow-up sample of 171 KLS cases, the TRANK1 rs71947865 was significantly associated with KLS in the subset follow-up sample of 59 KLS cases who reported birth difficulties (OR=1.54;p=0.01). Genetic liability of KLS as explained by polygenic risk scores was increased (pseudo r2=0.15;p<2.0x10-22 at p=0.5 threshold) in the follow-up sample. Pathway analysis of genetic associations identified enrichment of circadian regulation pathway genes in KLS cases. Our results suggest links between KLS, behavioral rhythmicity, and bipolar disorder, and indicates that the TRANK1 polymorphisms in conjunction with reported birth difficulties may predispose to KLS.

中文翻译：

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Kleine Levin综合征与TRANK1基因位点的出生困难和遗传变异有关。

克莱因-莱文综合症（KLS）是一种罕见的疾病，以严重的情节性失眠症为特征，伴有认知障碍并伴有冷漠或抑制。尽管影像学研究表明发作期间下丘脑/丘脑区域的活动减少，但病理生理学尚不清楚。家族发生率增加，并且危险性与出生困难的报道有关。我们对14年来收集的673例KLS病例进行了全球病例对照全基因组关联研究，并从种族上匹配了15341名对照个体。我们发现与20个单核苷酸多态性之间存在强大的全基因组显着关联（OR = 1.48，rs71947865，p = 8.6x10-9），其中20个单核苷酸多态性位于TRANK1基因3 [prime]区的35kb区域，以前与双相情感障碍和精神分裂症。惊人地 带有TRANK1 rs71947865变体的KLS病例的分娩困难报告显着增加。在过去40年中，随着围产期结局的显着改善，我们进一步按出生年份对样本进行分层，发现最近的病例中TRANK1 rs71947865的关联显着减少。尽管TRANK1 rs71947865关联在整个171名KLS病例的整个随访样本中均未复制，但TRANK1 rs71947865与报告出生困难的59例KLS病例的子随访样本中的KLS显着相关（OR = 1.54; p = 0.01）。在后续样本中，由多基因风险评分所解释的KLS的遗传责任感有所增加（伪r2 = 0.15；在p = 0.5阈值时p <2.0x10-22）。遗传协会的通路分析确定了KLS病例中的昼夜节律调节通路基因丰富。