Kleine-Levin syndrome is associated with birth difficulties and genetic variants in the TRANK1 gene lociStanford Univ, CA 94304 USA.
Stanford Univ, CA 94305 USA; Stanford Univ, CA 94305 USA.
Kleine Levin Syndrome Fdn, MA 02468 USA.
Stanford Univ, CA 94304 USA.
Stanford Univ, CA 94304 USA.
Stanford Univ, CA 94304 USA.
Stanford Univ, CA 94305 USA; Vet Affairs Palo Alto Hlth Care Syst, CA 94304 USA.
Chang Gung Mem Hosp & Univ, Taiwan; Chang Gung Mem Hosp & Univ, Taiwan.
Peking Univ Peoples Hosp, Peoples R China.
Tel Aviv Univ, Israel.
Hosp Robert Debre, France; Hosp Robert Debre, France.
Sorbonne Univ, France.
Tokyo Metropolitan Inst Med Sci, Japan.
Maynei Hayeshua Med Ctr, Israel; Tel Aviv Univ, Israel.
Charles Univ Prague, Czech Republic.
Univ Bologna, Italy; IRCCS, Italy.
Univ Tsukuba, Japan.
Univ Complutense Madrid, Spain; Univ Complutense Madrid, Spain.
Guys Hosp, England; Kings Coll London, England.
Univ Sao Paulo, Brazil.
Hosp Univ Son Espases, Spain.
Nagoya City Univ, Japan.
Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Uppsala Univ, Sweden.
Hop Univ Strasbourg, France.
Emory Univ, GA 30322 USA.
Blood Ctr Community Madrid, Spain.
Innsbruck Med Univ, Austria.
Catholic Univ Korea, South Korea.
Univ Bologna, Italy; IRCCS, Italy.
Philipps Univ Marburg, Germany.
Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Neurologiska kliniken i Linköping. Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Uppsala Univ, Sweden.
Univ Montpellier, France; Univ Montpellier, France.
Sorbonne Univ, France.
Stanford Univ, CA 94304 USA.
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2021 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 118, no 12, article id e2005753118Article in journal (Refereed) Published
Abstract [en]
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 x 10(-9)) within the 3region 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 R-2 = 0.15; P < 2.0 x 10(-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, circadian regulation, and bipolar disorder, and indicate that the TRANK1 polymorphisms in conjunction with reported birth difficulties may predispose to KLS.
Place, publisher, year, edition, pages
NATL ACAD SCIENCES , 2021. Vol. 118, no 12, article id e2005753118
Keywords [en]
Kleine-Levin syndrome; hypersomnia; bipolar disorder; birth difficulties; GWAS
National Category
Medical Genetics and Genomics
Identifiers
URN: urn:nbn:se:liu:diva-175081DOI: 10.1073/pnas.2005753118ISI: 000631868600003PubMedID: 33737391Scopus ID: 2-s2.0-85103146380OAI: oai:DiVA.org:liu-175081DiVA, id: diva2:1545794
Note
Funding Agencies|NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [1R01MH080957, 1S10OD023452-01]; French Ministry of Health [PHRC 070138]; Academy of FinlandAcademy of FinlandEuropean Commission [309643]; Yrjo Jahnsson Foundation; Oskar Oflund Foundation; KLSF
2021-04-202021-04-202025-02-10Bibliographically approved