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 × 10-22 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.

Center for Sleep Sciences and Medicine Stanford University School of Medicine Palo Alto CA 94304

Center for Sleep Sciences and Medicine Stanford University School of Medicine Palo Alto CA 94304;

Department of Biomedical and Clinical Sciences Linköping University Linköping 581 83 Sweden

Department of Biomedical and Neuromotor Sciences University of Bologna 40139 Bologna Italy

Department of Child Psychiatry Chang Gung Memorial Hospital and University Taoyuan 33305 Taiwan

Department of Neurology 1st Faculty of Medicine General Teaching Hospital Charles University Prague 116 36 Czech Republic

Department of Neurology and Neurological Sciences Stanford University Stanford CA 94305

Department of Neurology Emory University Atlanta GA 30322

Department of Neurology Innsbruck Medical University 6020 Innsbruck Austria

Department of Neurology Maynei Hayeshua Medical Center 5154475 Bnei Barak Israel

Department of Neuropharmacology Nagoya City University Nagoya 467 8601 Japan

Department of Neuropsychiatry College of Medicine St Vincent's Hospital Catholic University of Korea Seoul 16247 Korea

Department of Neuroscience Uppsala University Uppsala 752 36 Sweden

Department of Psychiatry and Behavioral Sciences Stanford University Stanford CA 94305

Department of Pulmonary Medicine Peking University People's Hospital Beijing 100044 China

Fundació Institut d'Investigació Sanitària Illes Balears Hospital Universitari Son Espases 07120 Palma Spain

Hephata Klinik Philipps Universität Marburg 35037 Marburg Germany

Histocompatibility Department Blood Center of the Community of Madrid 28032 Madrid Spain

Hospital Universitario e Instituto de Investigación Gregorio Marañón Universidad Complutense de Madrid 28040 Madrid Spain

Institute for Neurosciences of Montpellier Universitaire de Montpellier INSERM 34000 Montpellier France

Institute of Psychiatry Hospital das Clinicas Faculty of Medicine University of Sao Paulo Sao Paulo 05403 010 Brazil

Institute of Psychiatry Psychology and Neuroscience King's College London SE5 8AF London United Kingdom

International Institute for Integrative Sleep Medicine University of Tsukuba Tsukuba 305 0005 Japan

Istituto di Ricovero e Cura a Carattere Scientifico IRCCS Institute of Neurological Sciences 40139 Bologna Italy

Kleine Levin Syndrome Foundation Boston MA 02468

Narcolepsy Rare Hypersomnias Sleep Unit Department of Neurology National Reference Centre for Orphan Diseases Centre Hospitalier Universitaire de Montpellier Universitaire de Montpellier 34000 Montpellier France

National Reference Center Hospital Robert Debre France Center for Narcolepsy and Idiopathic Hypersomnia 75019 Paris France

Pediatric Sleep Center Hospital Robert Debre France Center for Narcolepsy and Idiopathic Hypersomnia 75019 Paris France

Safra Children's Hospital Sheba Medical Center Sackler Faculty of Medicine Tel Aviv University 52621 Tel Aviv Israel

Sierra Pacific Mental Illness Research Education and Clinical Center Veterans Affairs Palo Alto Health Care System Palo Alto CA 94304

Sleep Center Chang Gung Memorial Hospital and University Taoyuan 33305 Taiwan

Sleep Disorders Center Hôpitaux Universitaires de Strasbourg 67091 Strasbourg France

Sleep Disorders Centre Guy's Hospital SE1 9RT London United Kingdom

Sleep Disorders Pitié Salpêtrière Hospital Assistance Publique Hôpitaux de Paris Sorbonne National Reference Center for Narcolepsy Idiopathic Hypersomnia and Kleine Levin Syndrome Sorbonne University Institut Hospitalo Universitaire A Institut du Cerveau et de la Moelle F 75013 Paris France

Sleep Disorders Project Department of Psychiatry and Behavioral Sciences Tokyo Metropolitan Institute of Medical Science Tokyo 156 8506 Japan

The Sackler Faculty of Medicine Tel Aviv University 6997801 Tel Aviv Israel

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Kleine D. W., Periodische Schlafsucht. Eur. Neurol. 57, 305–320 (1925).

Levin M., Periodic somnolence and morbid hunger: A new syndrome. Brain 59, 494–504 (1936).

Arnulf I., et al. ., Kleine-Levin syndrome: A systematic study of 108 patients. Ann. Neurol. 63, 482–493 (2008). PubMed

Arnulf I., Rico T. J., Mignot E., Diagnosis, disease course, and management of patients with Kleine-Levin syndrome. Lancet Neurol. 11, 918–928 (2012). PubMed

Billiard M., Jaussent I., Dauvilliers Y., Besset A., Recurrent hypersomnia: A review of 339 cases. Sleep Med. Rev. 15, 247–257 (2011). PubMed

Arnulf I., Zeitzer J. M., File J., Farber N., Mignot E., Kleine-Levin syndrome: A systematic review of 186 cases in the literature. Brain 128, 2763–2776 (2005). PubMed

Leu-Semenescu S., et al. ., Lithium therapy in Kleine-Levin syndrome: An open-label, controlled study in 130 patients. Neurology 85, 1655–1662 (2015). PubMed

Huang Y. S., et al. ., Relationship between Kleine-Levin syndrome and upper respiratory infection in Taiwan. Sleep (Basel) 35, 123–129 (2012). PubMed PMC

Nguyen Q. T., et al. ., Familial Kleine-Levin syndrome: A specific entity? Sleep (Basel) 39, 1535–1542 (2016). PubMed PMC

Peraita-Adrados R., Vicario J. L., Tafti M., García de León M., Billiard M., Monozygotic twins affected with Kleine-Levin syndrome. Sleep (Basel) 35, 595–596 (2012). PubMed PMC

Habra O., Heinzer R., Haba-Rubio J., Rossetti A. O., Prevalence and mimics of Kleine-Levin syndrome: A survey in French-speaking Switzerland. J. Clin. Sleep Med. 12, 1083–1087 (2016). PubMed PMC

Dauvilliers Y., et al. ., Kleine-Levin syndrome: An autoimmune hypothesis based on clinical and genetic analyses. Neurology 59, 1739–1745 (2002). PubMed

Lavault S., et al. ., Kleine-Levin syndrome in 120 patients: Differential diagnosis and long episodes. Ann. Neurol. 77, 529–540 (2015). PubMed

Lam M.et al. .; Schizophrenia Working Group of the Psychiatric Genomics Consortium; Indonesia Schizophrenia Consortium; Genetic REsearch on schizophreniA neTwork-China and the Netherlands (GREAT-CN) , Comparative genetic architectures of schizophrenia in East Asian and European populations. Nat. Genet. 51, 1670–1678 (2019). PubMed PMC

Stahl E. A.et al. .; eQTLGen Consortium; BIOS Consortium; Bipolar Disorder Working Group of the Psychiatric Genomics Consortium , Genome-wide association study identifies 30 loci associated with bipolar disorder. Nat. Genet. 51, 793–803 (2019). PubMed PMC

Ikeda M., et al. ., Genome-wide association study detected novel susceptibility genes for schizophrenia and shared trans-populations/diseases genetic effect. Schizophr. Bull. 45, 824–834 (2019). PubMed PMC

Stilo S. A., Murray R. M., Non-genetic factors in schizophrenia. Curr. Psychiatry Rep. 21, 100 (2019). PubMed PMC

Söderlund J., Wicks S., Jörgensen L., Dalman C., Comparing cohort incidence of schizophrenia with that of bipolar disorder and affective psychosis in individuals born in Stockholm County 1955-1967. Psychol. Med. 45, 3433–3439 (2015). PubMed

Chudal R., et al. ., Perinatal factors and the risk of bipolar disorder in Finland. J. Affect. Disord. 155, 75–80 (2014). PubMed PMC

Haukvik U. K., et al. ., Pre- and perinatal hypoxia associated with hippocampus/amygdala volume in bipolar disorder. Psychol. Med. 44, 975–985 (2014). PubMed PMC

Nosarti C., et al. ., Preterm birth and psychiatric disorders in young adult life. Arch. Gen. Psychiatry 69, E1–E8 (2012). PubMed

McGrath J., Scott J., Urban birth and risk of schizophrenia: A worrying example of epidemiology where the data are stronger than the hypotheses. Epidemiol. Psichiatr. Soc. 15, 243–246 (2006). PubMed

Cannon M., Jones P. B., Murray R. M., Obstetric complications and schizophrenia: Historical and meta-analytic review. Am. J. Psychiatry 159, 1080–1092 (2002). PubMed

Kunugi H., Nanko S., Murray R. M., Obstetric complications and schizophrenia: Prenatal underdevelopment and subsequent neurodevelopmental impairment. Br. J. Psychiatry Suppl. 40, s25–s29 (2001). PubMed

Kinney D. K., Yurgelun-Todd D. A., Tohen M., Tramer S., Pre- and perinatal complications and risk for bipolar disorder: A retrospective study. J. Affect. Disord. 50, 117–124 (1998). PubMed

Geddes J. R., Lawrie S. M., Obstetric complications and schizophrenia: A meta-analysis. Br. J. Psychiatry 167, 786–793 (1995). PubMed

McNeil T. F., Perinatal risk factors and schizophrenia: Selective review and methodological concerns. Epidemiol. Rev. 17, 107–112 (1995). PubMed

Brixey S. N., Gallagher B. J. 3rd, McFalls J. A. Jr., Parmelee L. F., Gestational and neonatal factors in the etiology of schizophrenia. J. Clin. Psychol. 49, 447–456 (1993). PubMed

Shimizu H., Hirose A., Tatsuno T., Nakamura M., Katsube J., Pharmacological properties of SM-3997: A new anxioselective anxiolytic candidate. Jpn. J. Pharmacol. 45, 493–500 (1987). PubMed

GTEx Consortium , The genotype-tissue expression (GTEx) project. Nat. Genet. 45, 580–585 (2013). PubMed PMC

Ursini G., et al. ., Convergence of placenta biology and genetic risk for schizophrenia. Nat. Med. 24, 792–801 (2018). PubMed

Peng S., et al. ., Expression quantitative trait loci (eQTLs) in human placentas suggest developmental origins of complex diseases. Hum. Mol. Genet. 26, 3432–3441 (2017). PubMed PMC

Hoffmann T. J., et al. ., Next generation genome-wide association tool: Design and coverage of a high-throughput European-optimized SNP array. Genomics 98, 79–89 (2011). PubMed PMC

Sander A., Wauer R., From single-case analysis of neonatal deaths toward a further reduction of the neonatal mortality rate. J. Perinat. Med. 47, 125–133 (2018). PubMed

Sugai M. K., Gilmour S., Ota E., Shibuya K., Trends in perinatal mortality and its risk factors in Japan: Analysis of vital registration data, 1979-2010. Sci. Rep. 7, 46681 (2017). PubMed PMC

Schneider E. B., Fetal health stagnation: Have health conditions in utero improved in the United States and Western and Northern Europe over the past 150 years? Soc. Sci. Med. 179, 18–26 (2017). PubMed

Verstraete E., et al. ., Healthcare-associated bloodstream infections in a neonatal intensive care unit over a 20-year period (1992-2011): Trends in incidence, pathogens, and mortality. Infect. Control Hosp. Epidemiol. 35, 511–518 (2014). PubMed

Glinianaia S. V., et al. ., Temporal changes in key maternal and fetal factors affecting birth outcomes: A 32-year population-based study in an industrial city. BMC Pregnancy Childbirth 8, 39 (2008). PubMed PMC

Rush D., Alvir J. M., Kenny D. A., Johnson S. S., Horvitz D. G., The National WIC evaluation: Evaluation of the special supplemental food program for women, infants, and children. III. Historical study of pregnancy outcomes. Am. J. Clin. Nutr. 48, 412–428 (1988). PubMed

Secolin R., et al. ., Family-based association study for bipolar affective disorder. Psychiatr. Genet. 20, 126–129 (2010). PubMed

Charney A. W., et al. ., Evidence for genetic heterogeneity between clinical subtypes of bipolar disorder. Transl. Psychiatry 7, e993 (2017). PubMed PMC

Hou L., et al. ., Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder. Hum. Mol. Genet. 25, 3383–3394 (2016). PubMed PMC

Mühleisen T. W., et al. ., Genome-wide association study reveals two new risk loci for bipolar disorder. Nat. Commun. 5, 3339 (2014). PubMed

Ruderfer D. M.et al. .; Schizophrenia Working Group of the Psychiatric Genomics Consortium; Bipolar Disorder Working Group of the Psychiatric Genomics Consortium; Cross-Disorder Working Group of the Psychiatric Genomics Consortium , Polygenic dissection of diagnosis and clinical dimensions of bipolar disorder and schizophrenia. Mol. Psychiatry 19, 1017–1024 (2014). PubMed PMC

Li Z., et al. ., Genome-wide association analysis identifies 30 new susceptibility loci for schizophrenia. Nat. Genet. 49, 1576–1583 (2017). PubMed

Schizophrenia Working Group of the Psychiatric Genomics Consortium , Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421–427 (2014). PubMed PMC

Chen D. T.et al. .; BiGS , Genome-wide association study meta-analysis of European and Asian-ancestry samples identifies three novel loci associated with bipolar disorder. Mol. Psychiatry 18, 195–205 (2013). PubMed

Choi S. W., O’Reilly P. F., PRSice-2: Polygenic Risk Score software for biobank-scale data. Gigascience 8, giz082 (2019). PubMed PMC

Ruderfer D. M., et al. ., Genomic dissection of bipolar disorder and schizophrenia, including 28 subphenotypes. Cell 173, 1705–1715.e16 (2018). PubMed PMC

Jones S. E., et al. ., Genome-wide association analyses of chronotype in 697,828 individuals provides insights into circadian rhythms. Nat. Commun. 10, 343 (2019). PubMed PMC

Dashti H. S., et al. ., Genome-wide association study identifies genetic loci for self-reported habitual sleep duration supported by accelerometer-derived estimates. Nat. Commun. 10, 1100 (2019). PubMed PMC

Wang H., et al. ., Genome-wide association analysis of self-reported daytime sleepiness identifies 42 loci that suggest biological subtypes. Nat. Commun. 10, 3503 (2019). PubMed PMC

de Leeuw C. A., Mooij J. M., Heskes T., Posthuma D., MAGMA: Generalized gene-set analysis of GWAS data. PLoS Comput. Biol. 11, e1004219 (2015). PubMed PMC

Giguère V., et al. ., Isoform-specific amino-terminal domains dictate DNA-binding properties of ROR alpha, a novel family of orphan hormone nuclear receptors. Genes Dev. 8, 538–553 (1994). PubMed

Griffin P., et al. ., Circadian clock protein Rev-erbα regulates neuroinflammation. Proc. Natl. Acad. Sci. U.S.A. 116, 5102–5107 (2019). PubMed PMC

Zhang Y., et al. ., GENE REGULATION. Discrete functions of nuclear receptor Rev-erbα couple metabolism to the clock. Science 348, 1488–1492 (2015). PubMed PMC

Solt L. A., Kojetin D. J., Burris T. P., The REV-ERBs and RORs: Molecular links between circadian rhythms and lipid homeostasis. Future Med. Chem. 3, 623–638 (2011). PubMed PMC

Guillaumond F., Dardente H., Giguère V., Cermakian N., Differential control of Bmal1 circadian transcription by REV-ERB and ROR nuclear receptors. J. Biol. Rhythms 20, 391–403 (2005). PubMed

Sato T. K., et al. ., A functional genomics strategy reveals Rora as a component of the mammalian circadian clock. Neuron 43, 527–537 (2004). PubMed

Al Shareef S. M., et al. ., Kleine-Levin syndrome is associated with LMOD3 variants. J. Sleep Res. 28, e12718 (2019). PubMed

Cingolani P., et al. ., A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly (Austin) 6, 80–92 (2012). PubMed PMC

Schatz U. A., et al. ., Evidence of mild founder LMOD3 mutations causing nemaline myopathy 10 in Germany and Austria. Neurology 91, e1690–e1694 (2018). PubMed

Tillman R., Geller B., Definitions of rapid, ultrarapid, and ultradian cycling and of episode duration in pediatric and adult bipolar disorders: A proposal to distinguish episodes from cycles. J. Child Adolesc. Psychopharmacol. 13, 267–271 (2003). PubMed

Groos E., et al. ., Emerging psychiatric disorders in Kleine-Levin syndrome. J. Sleep Res. 27, e12690 (2018). PubMed

Kaplan K. A., et al. ., Hypersomnia subtypes, sleep and relapse in bipolar disorder. Psychol. Med. 45, 1751–1763 (2015). PubMed PMC

Grigolon R. B., et al. ., Hypersomnia and bipolar disorder: A systematic review and meta-analysis of proportion. J. Affect. Disord. 246, 659–666 (2019). PubMed

Pagani L., et al. ., Genetic contributions to circadian activity rhythm and sleep pattern phenotypes in pedigrees segregating for severe bipolar disorder. Proc. Natl. Acad. Sci. U.S.A. 113, E754–E761 (2016). PubMed PMC

Bora E., Neurocognitive features in clinical subgroups of bipolar disorder: A meta-analysis. J. Affect. Disord. 229, 125–134 (2018). PubMed

Lima I. M. M., Peckham A. D., Johnson S. L., Cognitive deficits in bipolar disorders: Implications for emotion. Clin. Psychol. Rev. 59, 126–136 (2018). PubMed PMC

Lane J. M., et al. ., Genome-wide association analyses of sleep disturbance traits identify new loci and highlight shared genetics with neuropsychiatric and metabolic traits. Nat. Genet. 49, 274–281 (2017). PubMed PMC

Lewis K. J. S., et al. ., Comparison of genetic liability for sleep traits among individuals with bipolar disorder I or II and control participants. JAMA Psychiatry 77, 303–310 (2019). PubMed PMC

Engström M., Latini F., Landtblom A. M., Neuroimaging in the Kleine-Levin syndrome. Curr. Neurol. Neurosci. Rep. 18, 58 (2018). PubMed PMC

Hong S. B., Neuroimaging of narcolepsy and Kleine-Levin syndrome. Sleep Med. Clin. 12, 359–368 (2017). PubMed

Kas A., Lavault S., Habert M. O., Arnulf I., Feeling unreal: A functional imaging study in patients with Kleine-Levin syndrome. Brain 137, 2077–2087 (2014). PubMed

Blume C., Garbazza C., Spitschan M., Effects of light on human circadian rhythms, sleep and mood. Somnologie (Berl.) 23, 147–156 (2019). PubMed PMC

Czeisler C. A., Zimmerman J. C., Ronda J. M., Moore-Ede M. C., Weitzman E. D., Timing of REM sleep is coupled to the circadian rhythm of body temperature in man. Sleep 2, 329–346 (1980). PubMed

Carskadon M. A., Dement W. C., Sleep studies on a 90-minute day. Electroencephalogr. Clin. Neurophysiol. 39, 145–155 (1975). PubMed

Goldbart A., et al. ., Narcolepsy and predictors of positive MSLTs in the Wisconsin sleep cohort. Sleep (Basel) 37, 1043–1051 (2014). PubMed PMC

Chen L., Huang Y.-S., “Actigraphy study and different hypersomnia disorders” in 2nd Asian Narcolepsy & Hypersomnolence Society Meeting (2019), vol. 2, p. 39.

Gold A. K., Kinrys G., Treating circadian rhythm disruption in bipolar disorder. Curr. Psychiatry Rep. 21, 14 (2019). PubMed PMC

Vreeker A., et al. ., Genetic analysis of activity, brain and behavioral associations in extended families with heavy genetic loading for bipolar disorder. Pyschol. Med., 1–9, 10.1017/S0033291719003416 (2019). PubMed DOI

Ikeda M., et al. ., A genome-wide association study identifies two novel susceptibility loci and trans population polygenicity associated with bipolar disorder. Mol. Psychiatry 23, 639–647 (2018). PubMed PMC

Psychiatric GWAS Consortium Bipolar Disorder Working Group , Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nat. Genet. 43, 977–983 (2011). PubMed PMC

Forstner A. J., et al. ., Identification of shared risk loci and pathways for bipolar disorder and schizophrenia. PLoS One 12, e0171595 (2017). PubMed PMC

Ripke S.et al. .; Multicenter Genetic Studies of Schizophrenia Consortium; Psychosis Endophenotypes International Consortium; Wellcome Trust Case Control Consortium 2 , Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat. Genet. 45, 1150–1159 (2013). PubMed PMC

Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium , Genome-wide association study identifies five new schizophrenia loci. Nat. Genet. 43, 969–976 (2011). PubMed PMC

Ward J., et al. ., Genome-wide analysis in UK Biobank identifies four loci associated with mood instability and genetic correlation with major depressive disorder, anxiety disorder and schizophrenia. Transl. Psychiatry 7, 1264 (2017). PubMed PMC

Weber G., Investigation of metal-species (Ca, Mg, Zn, Fe, Cu, Pb, Cd, Sn) in urine by HPLC-AAS. J. Trace Elem. Electrolytes Health Dis. 2, 61–65 (1988). PubMed

Tsuchiya K. J., Byrne M., Mortensen P. B., Risk factors in relation to an emergence of bipolar disorder: A systematic review. Bipolar Disord. 5, 231–242 (2003). PubMed

Lyall D. M., et al. ., Low birth weight and features of neuroticism and mood disorder in 83 545 participants of the UK Biobank cohort. BJPsych Open 2, 38–44 (2016). PubMed PMC

Kikas T., Rull K., Beaumont R. N., Freathy R. M., Laan M., The effect of genetic variation on the placental transcriptome in humans. Front. Genet. 10, 550 (2019). PubMed PMC

Brockenshire A., The “mini-mental state”: A handy tool. Perspectives 11, 7–8 (1987). PubMed

Horikoshi M.et al. .; CHARGE Consortium Hematology Working Group; Early Growth Genetics (EGG) Consortium , Genome-wide associations for birth weight and correlations with adult disease. Nature 538, 248–252 (2016). PubMed PMC

Warrington N. M.et al. .; EGG Consortium , Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors. Nat. Genet. 51, 804–814 (2019). PubMed PMC

Beaumont R. N.et al. .; Early Growth Genetics (EGG) Consortium , Genome-wide association study of offspring birth weight in 86 577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics. Hum. Mol. Genet. 27, 742–756 (2018). PubMed PMC

Zhang G., et al. ., Genetic associations with gestational duration and spontaneous preterm birth. N. Engl. J. Med. 377, 1156–1167 (2017). PubMed PMC

Srinivasan L.et al. .; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network , Genome-wide association study of sepsis in extremely premature infants. Arch. Dis. Child. Fetal Neonatal Ed. 102, F439–F445 (2017). PubMed PMC

Pasqualini J. R., Mercat P., Giambiagi N., Histone acetylation decreased by estradiol in the MCF-7 human mammary cancer cell line. Breast Cancer Res. Treat. 14, 101–105 (1989). PubMed

Jiang X., et al. ., Sodium valproate rescues expression of TRANK1 in iPSC-derived neural cells that carry a genetic variant associated with serious mental illness. Mol. Psychiatry 24, 613–624 (2019). PubMed PMC

Purcell S., et al. ., PLINK: A tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007). PubMed PMC

Nicolazzi E. L., Iamartino D., Williams J. L., AffyPipe: An open-source pipeline for Affymetrix Axiom genotyping workflow. Bioinformatics 30, 3118–3119 (2014). PubMed PMC

Auton A.et al. .; 1000 Genomes Project Consortium , A global reference for human genetic variation. Nature 526, 68–74 (2015). PubMed PMC

Delaneau O., Marchini J., Zagury J. F., A linear complexity phasing method for thousands of genomes. Nat. Methods 9, 179–181 (2011). PubMed

Delaneau O., Marchini J.; 1000 Genomes Project Consortium; 1000 Genomes Project Consortium , Integrating sequence and array data to create an improved 1000 Genomes Project haplotype reference panel. Nat. Commun. 5, 3934 (2014). PubMed PMC

Howie B. N., Donnelly P., Marchini J., A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet. 5, e1000529 (2009). PubMed PMC

Marchini J., Howie B., Myers S., McVean G., Donnelly P., A new multipoint method for genome-wide association studies by imputation of genotypes. Nat. Genet. 39, 906–913 (2007). PubMed

Watanabe K., Taskesen E., van Bochoven A., Posthuma D., Functional mapping and annotation of genetic associations with FUMA. Nat. Commun. 8, 1826 (2017). PubMed PMC

Turner S. D., qqman: An R package for visualizing GWAS results using Q-Q and manhattan plots. bioRxiv [Preprint] (2014). 10.1101/005165 (Accessed 20 March 2019). DOI

Arnold M., Raffler J., Pfeufer A., Suhre K., Kastenmüller G., SNiPA: An interactive, genetic variant-centered annotation browser. Bioinformatics 31, 1334–1336 (2015). PubMed PMC

Hormozdiari F., et al. ., Colocalization of GWAS and eQTL signals detects target genes. Am. J. Hum. Genet. 99, 1245–1260 (2016). PubMed PMC

Zheng J.et al. .; Early Genetics and Lifecourse Epidemiology (EAGLE) Eczema Consortium , LD hub: A centralized database and web interface to perform LD score regression that maximizes the potential of summary level GWAS data for SNP heritability and genetic correlation analysis. Bioinformatics 33, 272–279 (2017). PubMed PMC

Li H., Durbin R., Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754–1760 (2009). PubMed PMC

Wang K., Li M., Hakonarson H., ANNOVAR: Functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 38, e164 (2010). PubMed PMC

Lee S., Abecasis G. R., Boehnke M., Lin X., Rare-variant association analysis: Study designs and statistical tests. Am. J. Hum. Genet. 95, 5–23 (2014). PubMed PMC

Central Disorders of Hypersomnolence: Association with Fatigue, Depression and Sleep Inertia Prevailing in Women

See more in PubMed

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