Kleine Levin syndrome is associated with birth difficulties and genetic variants in the TRANK1 gene loci
Authors: Ambati Aditya , Hillary Ryan , Leu-Semenescu Smaranda , Ollila Hanna M. , Lin Ling , During Emmanuel , Farber Neal , Rico Thomas J , Faraco Juliette , Leary Eileen , Goldstein-Piekarski Andrea , Huang Yu-Shu , Han Fang , Sivan Yakov , Lecendreux Michel , Dodet Pauline , Honda Makoto , Gadoth Natan , Nevsimalova Sona , Pizza Fabio , Kanbayashi Takashi , Adrados Rosa Peraita , Leschziner Guy , Hasan Rosa , Canellas Francesca , Kume Kazuhiko , Daniilidou Makrina , Bourgin Patrice , Rye David , Vicario José L , Högl Birgit , Hong Seung Chul , Plazzi Guiseppe , Mayer Geert , Landtblom Anne Marie , Dauvilliers Yves , Arnulf Isabelle , Mignot Emmanuel 
Published: January 2021

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=8.6×10−9) with 20 single nucleotide polymorphisms encompassing a 35kb region located in the 3’ region ofTRANK1gene, previously associated with bipolar disorder and schizophrenia. Strikingly, KLS cases withTRANK1rs71947865 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 reducedTRANK1rs71947865 association. While theTRANK1rs71947865 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<2.0×10−22at 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 theTRANK1polymorphisms in conjunction with reported birth difficulties may predispose to KLS.

Significance Statement

Genetic markers inTRANK1gene and its vicinity have been weakly associated with bipolar disorder and schizophrenia (10% increased risk). We found that the same polymorphisms are associated with Kleine-Levin Syndrome (50% increased risk), a rare sleep disorder characterized by recurrent episodes of severe hypersomnia and cognitive abnormalities. Response to lithium treatment are suggestive of a pathophysiological overlap between KLS and bipolar disorder. The study also shows that variants in theTRANK1gene region may predispose to KLS when patients have had a difficult birth, suggesting thatTRANK1gene region modulate newborns’ response to brain injury, with consequences for mental and neurological health in adulthood. Another possibility may be that the polymorphism impact birth and KLS.