A Variant at 9q34.11 is Associated with HLA-DQB1*06:02 negative Essential Hypersomnia

Essential hypersomnia (EHS) is a lifelong disorder characterized by excessive daytime sleepiness without cataplexy. EHS is associated with human leukocyte antigen (HLA)-DQB1*06:02, similar to narcolepsy with cataplexy (narcolepsy). Previous studies suggest that DQB1*06:02-positive and -negative EHS are different in terms of their clinical features and follow different pathological pathways. DQB1*06:02-positive EHS and narcolepsy share the same susceptibility genes. In the present study, we report a genome-wide association study with replication for DQB1*06:02-negative EHS (408 patients and 2247 healthy controls, all Japanese). One single-nucleotide polymorphism, rs10988217, which is located 15-kb upstream of carnitine O-acetyltransferase (CRAT), was significantly associated with DQB1*06:02-negative EHS (P = 7.5 × 10, odds ratio = 2.63). The risk allele of the disease-associated SNP was correlated with higher expression levels of CRAT in various tissues and cell types, including brain tissue. In addition, the risk allele was associated with levels of succinylcarnitine (P = 1.4 × 10) in human blood. The leading SNP in this region was the same in associations with both DQB1*06:02-negative EHS and succinylcarnitine levels. The results suggest that DQB1*06:02-negative EHS may be associated with an underlying dysfunction in energy metabolic pathways.

Citing Articles

Genome-wide association study of idiopathic hypersomnia in a Japanese population.

Tanida K, Shimada M, Khor S, Toyoda H, Kato K, Kotorii N Sleep Biol Rhythms. 2024; 20(1):137-148.

PMID: 38469065 PMC: 10899960. DOI: 10.1007/s41105-021-00349-2.

Polygenic risk score analysis revealed shared genetic background in attention deficit hyperactivity disorder and narcolepsy.

Takahashi N, Nishimura T, Harada T, Okumura A, Choi D, Iwabuchi T Transl Psychiatry. 2020; 10(1):284.

PMID: 32801330 PMC: 7429956. DOI: 10.1038/s41398-020-00971-7.

Genetics of narcolepsy.

Miyagawa T, Tokunaga K Hum Genome Var. 2019; 6:4.

PMID: 30652006 PMC: 6325123. DOI: 10.1038/s41439-018-0033-7.

References

Yoshida G, Li M, Horiuchi M, Nakagawa S, Sakata M, Kuchiiwa S . Fasting-induced reduction in locomotor activity and reduced response of orexin neurons in carnitine-deficient mice. Neurosci Res. 2006; 55(1):78-86. DOI: 10.1016/j.neures.2006.02.003. View

Miyagawa T, Kawashima M, Nishida N, Ohashi J, Kimura R, Fujimoto A . Variant between CPT1B and CHKB associated with susceptibility to narcolepsy. Nat Genet. 2008; 40(11):1324-8. DOI: 10.1038/ng.231. View

Miyata Y, Shimomura I . Metabolic flexibility and carnitine flux: The role of carnitine acyltransferase in glucose homeostasis. J Diabetes Investig. 2014; 4(3):247-9. PMC: 4015659. DOI: 10.1111/jdi.12064. View

Patterson N, Price A, Reich D . Population structure and eigenanalysis. PLoS Genet. 2006; 2(12):e190. PMC: 1713260. DOI: 10.1371/journal.pgen.0020190. View

Rizzo C, Boenzi S, Inglese R, la Marca G, Muraca M, Martinez T . Measurement of succinyl-carnitine and methylmalonyl-carnitine on dried blood spot by liquid chromatography-tandem mass spectrometry. Clin Chim Acta. 2013; 429:30-3. DOI: 10.1016/j.cca.2013.11.016. View

Burkhardt R, Kirsten H, Beutner F, Holdt L, Gross A, Teren A . Integration of Genome-Wide SNP Data and Gene-Expression Profiles Reveals Six Novel Loci and Regulatory Mechanisms for Amino Acids and Acylcarnitines in Whole Blood. PLoS Genet. 2015; 11(9):e1005510. PMC: 4581711. DOI: 10.1371/journal.pgen.1005510. View

Nishino S, Ripley B, Overeem S, Lammers G, Mignot E . Hypocretin (orexin) deficiency in human narcolepsy. Lancet. 2000; 355(9197):39-40. DOI: 10.1016/S0140-6736(99)05582-8. View

Komada Y, Inoue Y, Mukai J, Shirakawa S, Takahashi K, Honda Y . Difference in the characteristics of subjective and objective sleepiness between narcolepsy and essential hypersomnia. Psychiatry Clin Neurosci. 2005; 59(2):194-9. DOI: 10.1111/j.1440-1819.2005.01357.x. View

Jogl G, Tong L . Crystal structure of carnitine acetyltransferase and implications for the catalytic mechanism and fatty acid transport. Cell. 2003; 112(1):113-22. DOI: 10.1016/s0092-8674(02)01228-x. View

10.

Rubio J, de Bustos F, Molina J, Jimenez-Jimenez F, Benito-Leon J, Martin M . Cerebrospinal fluid carnitine levels in patients with Alzheimer's disease. J Neurol Sci. 1998; 155(2):192-5. DOI: 10.1016/s0022-510x(97)00314-6. View

11.

Mukai J, Uchida S, Miyazaki S, Nishihara K, Honda Y . Spectral analysis of all-night human sleep EEG in narcoleptic patients and normal subjects. J Sleep Res. 2003; 12(1):63-71. DOI: 10.1046/j.1365-2869.2003.00331.x. View

12.

Miyagawa T, Toyoda H, Kanbayashi T, Imanishi A, Sagawa Y, Kotorii N . An association analysis of HLA-DQB1 with narcolepsy without cataplexy and idiopathic hypersomnia with/without long sleep time in a Japanese population. Hum Genome Var. 2016; 2:15031. PMC: 4785567. DOI: 10.1038/hgv.2015.31. View

13.

Minkler P, Stoll M, Ingalls S, Kerner J, Hoppel C . Quantitative acylcarnitine determination by UHPLC-MS/MS--Going beyond tandem MS acylcarnitine "profiles". Mol Genet Metab. 2015; 116(4):231-41. PMC: 5009370. DOI: 10.1016/j.ymgme.2015.10.002. View

14.

Miyagawa T, Toyoda H, Hirataka A, Kanbayashi T, Imanishi A, Sagawa Y . New susceptibility variants to narcolepsy identified in HLA class II region. Hum Mol Genet. 2014; 24(3):891-8. DOI: 10.1093/hmg/ddu480. View

15.

Nishino S, Kanbayashi T . Symptomatic narcolepsy, cataplexy and hypersomnia, and their implications in the hypothalamic hypocretin/orexin system. Sleep Med Rev. 2005; 9(4):269-310. DOI: 10.1016/j.smrv.2005.03.004. View

16.

McCarroll S, Kuruvilla F, Korn J, Cawley S, Nemesh J, Wysoker A . Integrated detection and population-genetic analysis of SNPs and copy number variation. Nat Genet. 2008; 40(10):1166-74. DOI: 10.1038/ng.238. View

17.

Yamasaki M, Miyagawa T, Toyoda H, Khor S, Liu X, Kuwabara H . Evaluation of polygenic risks for narcolepsy and essential hypersomnia. J Hum Genet. 2016; 61(10):873-878. DOI: 10.1038/jhg.2016.65. View

18.

Miyagawa T, Miyadera H, Tanaka S, Kawashima M, Shimada M, Honda Y . Abnormally low serum acylcarnitine levels in narcolepsy patients. Sleep. 2011; 34(3):349-53A. PMC: 3041711. DOI: 10.1093/sleep/34.3.349. View

19.

Sasai T, Inoue Y, Komada Y, Sugiura T, Matsushima E . Comparison of clinical characteristics among narcolepsy with and without cataplexy and idiopathic hypersomnia without long sleep time, focusing on HLA-DRB1( *)1501/DQB1( *)0602 finding. Sleep Med. 2009; 10(9):961-6. DOI: 10.1016/j.sleep.2008.12.007. View

20.

Tafti M, Petit B, Chollet D, Neidhart E, de Bilbao F, Kiss J . Deficiency in short-chain fatty acid beta-oxidation affects theta oscillations during sleep. Nat Genet. 2003; 34(3):320-5. DOI: 10.1038/ng1174. View