Kleine-Levin syndrome is associated with birth difficulties and genetic variants in the TRANK1 gene loci

Aditya Ambati, Ryan Hillary, Smaranda Leu-Semenescu, Hanna M. Ollila, Ling Lin, Emmanuel H. During, Neal Farber, Thomas J. Rico, Juliette Faraco, Eileen Leary, Andrea N. Goldstein-Piekarski, Yu Shu Huang, Fang Han, Yakov Sivan, Michel Lecendreux, Pauline Dodet, Makoto Honda, Natan Gadoth, Sona Nevsimalova, Fabio PizzaTakashi Kanbayashi, Rosa Peraita-Adrados, Guy D. Leschziner, Rosa Hasan, Francesca Canellas, Kazuhiko Kume, Makrina Daniilidou, Patrice Bourgin, David Rye, Jose L. Vicario, Birgit Hogl, Seung Chul Hong, Guiseppe Plazzi, Geert Mayer, Anne Marie Landtblom, Yves Dauvilliers, Isabelle Arnulf, Emmanuel Jean Marie Mignot*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

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 y, and ethnically matched 15,341 control individuals. We found a strong genome-wide significant association (rs71947865, Odds Ratio [OR] = 1.48, P = 8.6 × 10-9) within the 3'region of TRANK1 gene locus, previously associated with bipolar disorder and schizophrenia. Strikingly, KLS cases with rs71947865 variant had significantly increased reports of a difficult birth. As perinatal outcomes have dramatically improved over the last 40 y, we further stratified our sample by birth years and found that recent cases had a significantly reduced rs71947865 association. While the rs71947865 association did not replicate in the entire follow-up sample of 171 KLS cases, 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, circadian regulation, and bipolar disorder, and indicate that the TRANK1 polymorphisms in conjunction with reported birth difficulties may predispose to KLS.

Original languageEnglish
Article numbere2005753118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number12
DOIs
StatePublished - 18 Mar 2021

Funding

FundersFunder number
KLSF
National Institutes of Health1R01MH080957 (2007−2013, PHRC 070138
NIH Office of the DirectorS10OD023452
Yrjö Jahnssonin Säätiö
Suomen Akatemia309643
Ministère des Affaires Sociales et de la Santé
Oskar Öflunds Stiftelse1S10OD023452-01

    Keywords

    • Bipolar disorder
    • Birth difficulties
    • GWAS
    • Hypersomnia
    • Kleine-Levin syndrome

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