Evaluation of polygenic risks for narcolepsy and essential hypersomnia

Abstract

In humans, narcolepsy is a sleep disorder that is characterized by sleepiness, cataplexy and rapid eye movement (REM) sleep abnormalities. Essential hypersomnia (EHS) is another type of sleep disorder that is characterized by excessive daytime sleepiness without cataplexy. A human leukocyte antigen (HLA) class II allele, HLA-DQB1*06:02, is a major genetic factor for narcolepsy. Almost all narcoleptic patients are carriers of this HLA allele, while 30–50% of EHS patients and 12% of all healthy individuals in Japan carry this allele. The pathogenesis of narcolepsy and EHS is thought to be partially shared. To evaluate the contribution of common single-nucleotide polymorphisms (SNPs) to narcolepsy onset and to assess the common genetic background of narcolepsy and EHS, we conducted a polygenic analysis that included 393 narcoleptic patients, 38 EHS patients with HLA-DQB1*06:02, 119 EHS patients without HLA-DQB1*06:02 and 1582 healthy individuals. We also included 376 individuals with panic disorder and 213 individuals with autism to confirm whether the results were biased. Polygenic risks in narcolepsy were estimated to explain 58.1% (PHLA-DQB1*06:02=2.30 × 10−48, Pwhole genome without HLA-DQB1*06:02=6.73 × 10−2) including HLA-DQB1*06:02 effects and 1.3% (Pwhole genome without HLA-DQB1*06:02=2.43 × 10−2) excluding HLA-DQB1*06:02 effects. The results also indicated that small-effect SNPs contributed to the development of narcolepsy. Reported susceptibility SNPs for narcolepsy in the Japanese population, CPT1B (carnitine palmitoyltransferase 1B), TRA@ (T-cell receptor alpha) and P2RY11 (purinergic receptor P2Y, G-protein coupled, 11), were found to explain 0.8% of narcolepsy onset (Pwhole genome without HLA-DQB1*06:02=9.74 × 10−2). EHS patients with HLA-DQB1*06:02 were estimated to have higher shared genetic background to narcoleptic patients than EHS patients without HLA-DQB1*06:02 even when the effects of HLA-DQB1*06:02 were excluded (EHS with HLA-DQB1*06:02: 40.4%, PHLA-DQB1*06:02=7.02 × 1014, Pwhole genome without HLA-DQB1*06:02=1.34 × 101, EHS without HLA-DQB1*06:02: 0.4%, Pwhole genome without HLA-DQB1*06:02=3.06 × 101). Meanwhile, the polygenic risks for narcolepsy could not explain the onset of panic disorder and autism, suggesting that our results were reasonable.

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References

  1. 1

    Mignot, E. Genetic and familial aspects of narcolepsy. Neurology 50, S16–S22 (1998).

    CAS  Article  Google Scholar 

  2. 2

    Overeem, S., Mignot, E., van Dijk, J. G. & Lammers, G. J. Narcolepsy: clinical features, new pathophysiologic insights, and future perspectives. J. Clin. Neurophysiol. 18, 78–105 (2001).

    CAS  Article  Google Scholar 

  3. 3

    Juji, T., Satake, M., Honda, Y. & Doi, Y. HLA antigens in Japanese patients with narcolepsy. All the patients were DR2 positive. Tissue Antigens 24, 316–319 (1984).

    CAS  Article  Google Scholar 

  4. 4

    Langdon, N., Welsh, K. I., van Dam, M., Vaughan, R. W. & Parkes, D. Genetic markers in narcolepsy. Lancet 2, 1178–1180 (1984).

    CAS  Article  Google Scholar 

  5. 5

    Matsuki, K., Juji, T., Tokunaga, K., Naohara, T., Satake, M. & Honda, Y. Human histocompatibility leukocyte antigen (HLA) haplotype frequencies estimated from the data on HLA class I, II, and III antigens in 111 Japanese narcoleptics. J. Clin. Invest. 76, 2078–2083 (1985).

    CAS  Article  Google Scholar 

  6. 6

    Miyagawa, T., Hohjoh, H., Honda, Y., Juji, T. & Tokunaga, K. Identification of a telomeric boundary of the HLA region with potential for predisposition to human narcolepsy. Immunogenetics 52, 12–18 (2000).

    CAS  Article  Google Scholar 

  7. 7

    Mignot, E., Lin, L., Rogers, W., Honda, Y., Qiu, X., Lin, X. et al. Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups. Am. J. Hum. Genet. 68, 686–699 (2001).

    CAS  Article  Google Scholar 

  8. 8

    Miyagawa, T., Kawashima, M., Nishida, N., Ohashi, J., Kimura, R., Fujimoto, A. et al. Variant between CPT1B and CHKB associated with susceptibility to narcolepsy. Nat. Genet. 40, 1324–1328 (2008).

    CAS  Article  Google Scholar 

  9. 9

    Hallmayer, J., Faraco, J., Lin, L., Hesselson, S., Winkelmann, J., Kawashima, M. et al. Narcolepsy is strongly associated with the T-cell receptor alpha locus. Nat. Genet. 41, 708–711 (2009).

    CAS  Article  Google Scholar 

  10. 10

    Kornum, B. R., Kawashima, M., Faraco, J., Lin, L., Rico, T. J., Hesselson, S. et al. Common variants in P2RY11 are associated with narcolepsy. Nat. Genet. 43, 66–71 (2011).

    CAS  Article  Google Scholar 

  11. 11

    Faraco, J., Lin, L., Kornum, B. R., Kenny, E. E., Trynka, G., Einen, M. et al. ImmunoChip study implicates antigen presentation to T cells in narcolepsy. PLoS Genet. 9, e1003270 (2013).

    CAS  Article  Google Scholar 

  12. 12

    Han, F., Faraco, J., Dong, X. S., Ollila, H. M., Lin, L., Li, J. et al. Genome wide analysis of narcolepsy in China implicates novel immune loci and reveals changes in association prior to versus after the 2009 H1N1 influenza pandemic. PLoS Genet. 9, e1003880 (2013).

    Article  Google Scholar 

  13. 13

    Chemelli, R. M., Willie, J. T., Sinton, C. M., Elmquist, J. K., Scammell, T., Lee, C. et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98, 437–451 (1999).

    CAS  Article  Google Scholar 

  14. 14

    Lin, L., Faraco, J., Li, R., Kadotani, H., Rogers, W., Lin, X. et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98, 365–376 (1999).

    CAS  Article  Google Scholar 

  15. 15

    Mignot, E., Lammers, G. J., Ripley, B., Okun, M., Nevsimalova, S., Overeem, S. et al. The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch. Neurol. 59, 1553–1562 (2002).

    Article  Google Scholar 

  16. 16

    Nishino, S., Ripley, B., Overeem, S., Lammers, G. J. & Mignot, E. Hypocretin (orexin) deficiency in human narcolepsy. Lancet 355, 39–40 (2000).

    CAS  Article  Google Scholar 

  17. 17

    Gencik, M., Dahmen, N., Wieczorek, S., Kasten, M., Bierbrauer, J., Anghelescu, I. et al. A prepro-orexin gene polymorphism is associated with narcolepsy. Neurology 56, 115–117 (2001).

    CAS  Article  Google Scholar 

  18. 18

    Olafsdottir, B. R., Rye, D. B., Scammell, T. E., Matheson, J. K., Stefansson, K. & Gulcher, J. R. Polymorphisms in hypocretin/orexin pathway genes and narcolepsy. Neurology 57, 1896–1899 (2001).

    CAS  Article  Google Scholar 

  19. 19

    Peyron, C., Faraco, J., Rogers, W., Ripley, B., Overeem, S., Charnay, Y. et al. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat. Med. 6, 991–997 (2000).

    CAS  Article  Google Scholar 

  20. 20

    Hungs, M., Lin, L., Okun, M. & Mignot, E. Polymorphisms in the vicinity of the hypocretin/orexin are not associated with human narcolepsy. Neurology 57, 1893–1895 (2001).

    CAS  Article  Google Scholar 

  21. 21

    Anderson, K. N., Pilsworth, S., Sharples, L. D., Smith, I. E. & Shneerson, J. M. Idiopathic hypersomnia: a study of 77 cases. Sleep 30, 1274–1281 (2007).

    Article  Google Scholar 

  22. 22

    Miyagawa, T., Honda, M., Kawashima, M., Shimada, M., Tanaka, S., Honda, Y. et al. Polymorphism located between CPT1B and CHKB, and HLA-DRB1*1501-DQB1*0602 haplotype confer susceptibility to CNS hypersomnias (essential hypersomnia). PLoS ONE 4, e5394 (2009).

    Article  Google Scholar 

  23. 23

    Honda, Y., Juji, T., Matsuki, K., Naohara, T., Satake, M., Inoko, H. et al. HLA-DR2 and Dw2 in narcolepsy and in other disorders of excessive somnolence without cataplexy. Sleep 9, 1–2 (1986).

    Article  Google Scholar 

  24. 24

    Honda, Y., Takahashi, Y., Honda, M., Watanabe, Y., Sato, T., Miki, T. et al in Sleep and Sleep Disorders: From Molecule to Behavior. (eds Inoue, S. & Hayashi, O.) 341–358 (Academic Press, New York, NY, USA, 1997).

    Google Scholar 

  25. 25

    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. 59, 194–199 (2005).

    Article  Google Scholar 

  26. 26

    Miyagawa, T., Honda, M., Kawashima, M., Shimada, M., Tanaka, S., Honda, Y. et al. Polymorphism located in TCRA locus confers susceptibility to essential hypersomnia with HLA-DRB1*1501-DQB1*0602 haplotype. J. Hum. Genet. 55, 63–65 (2010).

    CAS  Article  Google Scholar 

  27. 27

    Maher, B. Personal genomes: the case of the missing heritability. Nature 456, 18–21 (2008).

    CAS  Article  Google Scholar 

  28. 28

    Manolio, T. A., Collins, F. S., Cox, N. J., Goldstein, D. B., Hindorff, L. A., Hunter, D. J. et al. Finding the missing heritability of complex diseases. Nature 461, 747–753 (2009).

    CAS  Article  Google Scholar 

  29. 29

    Toyoda, H., Miyagawa, T., Koike, A., Kanbayashi, T., Imanishi, A., Sagawa, Y. et al. A polymorphism in CCR1/CCR3 is associated with narcolepsy. Brain Behav. Immun. 49, 148–155 (2015).

    CAS  Article  Google Scholar 

  30. 30

    Khor, S. S., Miyagawa, T., Toyoda, H., Yamasaki, M., Kawamura, Y., Tanii, H. et al. Genome-wide association study of HLA-DQB1*06:02 negative essential hypersomnia. PeerJ 1, e66 (2013).

    Article  Google Scholar 

  31. 31

    Otowa, T., Kawamura, Y., Nishida, N., Sugaya, N., Koike, A., Yoshida, E. et al. Meta-analysis of genome-wide association studies for panic disorder in the Japanese population. Transl. Psychiatry 2, e186 (2012).

    CAS  Article  Google Scholar 

  32. 32

    Liu, X. X., Kawamura, Y., Shimada, T., Otowa, T., Koishi, S., Sugiyama, T. et al. Association of the oxytocin receptor (OXTR) gene polymorphisms with autism spectrum disorder (ASD) in the Japanese population. J. Hum. Genet. 55, 137–141 (2010).

    CAS  Article  Google Scholar 

  33. 33

    Shiota, S., Tochigi, M., Shimada, H., Ohashi, J., Kasai, K., Kato, N. et al. Association and interaction analyses of NRG1 and ERBB4 genes with schizophrenia in a Japanese population. J. Hum. Genet. 53, 929–935 (2008).

    Article  Google Scholar 

  34. 34

    Tochigi, M., Zhang, X., Ohashi, J., Hibino, H., Otowa, T., Rogers, M. et al. Association study between the TNXB locus and schizophrenia in a Japanese population. Am. J. Med. Genet. B Neuropsychiatr. Genet. 144B, 305–309 (2007).

    Article  Google Scholar 

  35. 35

    Adachi, S., Tajima, A., Quan, J., Haino, K., Yoshihara, K., Masuzaki, H. et al. Meta-analysis of genome-wide association scans for genetic susceptibility to endometriosis in Japanese population. J. Hum. Genet. 55, 816–821 (2010).

    Article  Google Scholar 

  36. 36

    McCarroll, S. A., Kuruvilla, F. G., Korn, J. M., Cawley, S., Nemesh, J., Wysoker, A. et al. Integrated detection and population-genetic analysis of SNPs and copy number variation. Nat. Genet. 40, 1166–1174 (2008).

    CAS  Article  Google Scholar 

  37. 37

    Purcell, S., Neale, B., Todd-Brown, K., Thomas, L., Ferreira, M. A. R., Bender, D. et al. PLINK: A tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

    CAS  Article  Google Scholar 

  38. 38

    Patterson, N., Price, A. L. & Reich, D. Population structure and eigenanalysis. PLoS Genet. 2, 2074–2093 (2006).

    CAS  Article  Google Scholar 

  39. 39

    International HapMap Consortium The International HapMap Project. Nature 426, 789–796 (2003).

    Article  Google Scholar 

  40. 40

    Kundu, S., Aulchenko, Y. S., van Duijn, C. M. & Janssens, A. C. PredictABEL: an R package for the assessment of risk prediction models. Eur. J. Epidemiol. 26, 261–264 (2011).

    Article  Google Scholar 

  41. 41

    Austin, G. The New S Language - a programming environment for data-analysis and graphics. Econ. J. 100, 650–652 (1990).

    Article  Google Scholar 

  42. 42

    Yang, J., Lee, S. H., Goddard, M. E. & Visscher, P. M. GCTA: a tool for genome-wide complex trait analysis. Am. J. Hum. Genet. 88, 76–82 (2011).

    CAS  Article  Google Scholar 

  43. 43

    Pollmacher, T., Schulz, H., Geisler, P., Kiss, E., Albert, E. D., Schwarzfischer, F. et al. Discordant for narcolepsy. Sleep 13, 336–343 (1990).

    CAS  Article  Google Scholar 

  44. 44

    Gengler, N., VanVleck, L. D., MacNeil, M. D., Misztal, I. & Pariacote, F. A. Influence of dominance relationships on the estimation of dominance variance with sire-dam subclass effects. J. Anim. Sci. 75, 2885–2891 (1997).

    CAS  Article  Google Scholar 

  45. 45

    Palucci, V., Schaeffer, L. R., Miglior, F. & Osborne, V. Non-additive genetic effects for fertility traits in Canadian Holstein cattle (Open Access publication). Genet. Sel. Evol. 39, 181–193 (2007).

    Article  Google Scholar 

  46. 46

    Norris, D., Varona, L., Ngambi, J. W., Visser, D. P., Mbajiorgu, C. A. & Voordewind, S. F. Estimation of the additive and dominance variances in SA Duroc pigs. Livest. Sci. 131, 144–147 (2010).

    Article  Google Scholar 

  47. 47

    Kirino, Y., Bertsias, G., Ishigatsubo, Y., Mizuki, N., Tugal-Tutkun, I., Seyahi, E. et al. Genome-wide association analysis identifies new susceptibility loci for Behcet's disease and epistasis between HLA-B*51 and ERAP1. Nat. Genet. 45, 202–207 (2013).

    CAS  Article  Google Scholar 

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Acknowledgements

We thank all of the individuals who participated in this study. This study was supported by Grants-in-Aid for Young Scientists (A) (23689022), Scientific Research (B) (15H04709) and Scientific Research on Innovative Areas (22133008) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and Grants-in-Aid from ‘Takeda Science Foundation’ and ‘SENSHIN Medical Research Foundation’.

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Correspondence to Taku Miyagawa.

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Yamasaki, M., Miyagawa, T., Toyoda, H. et al. Evaluation of polygenic risks for narcolepsy and essential hypersomnia. J Hum Genet 61, 873–878 (2016). https://doi.org/10.1038/jhg.2016.65

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