A variant at 9q34.11 is associated with HLA-DQB1*06:02 negative essential hypersomnia

Miyagawa, Taku; Khor, Seik‐Soon; Toyoda, Hiromi; Kanbayashi, Takashi; Imanishi, Aya; Sagawa, Yohei; Kotorii, Nozomu; Kotorii, Tatayu; Ariyoshi, Yu; Hashizume, Yuji; Ogi, Kimihiro; Hiejima, Hiroshi; Kamei, Yuichi; Hida, Akiko; Miyamoto, Masayuki; Ikegami, Azusa; Wada, Yamato; Takami, Masanori; Higashiyama, Yuichi; Miyake, Ryoko; Kondo, Hideaki; Fujimura, Yota; Tamura, Yoshiyuki; Taniyama, Yukari; Omata, Naoto; Tanaka, Yuji; Moriya, Shunpei; Furuya, Hirokazu; Kato, Mitsuhiro; Kawamura, Yoshiya; Otowa, Takeshi; Miyashita, Akinori; Kojima, Hiroto; Saji, Hiroh; Shimada, Mihoko; Yamasaki, Makari; Kobayashi, Takumi; Misawa, Rumi; Shigematsu, Yosuke; Kuwano, Ryozo; Sasaki, Tsukasa; Ishigooka, Jun; Wada, Yuji; Tsuruta, Kazuhito; Tanaka, Fumiaki; Yamada, Naoto; Okawa, Masako; Kuroda, Kenji; Kume, Kazuhiko; Hirata, Koichi; Uchimura, Naohisa; Shimizu, Tetsuo; Inoue, Yuichi; Honda, Yoshiyuki; Mishima, Kazuo; Honda, Masashi; Tokunaga, Katsushi

doi:10.1038/s10038-018-0518-8

Cited by 5 publications

(2 citation statements)

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“…Capitalizing on the much higher prevalence of narcolepsy in the Japanese population (0.16-0.18%) 14 compared to the Caucasian population (0.02-0.06%) 15 , and using the previous Japanese GWAS study of narcolepsy as a discovery cohort, we investigated a possible genetic association between ADHD traits and narcolepsy in our birth cohort sample from the HBC study. We also conducted a polygenic risk analysis of ADHD traits using a summary from the previous GWAS study of essential hypersomnia (EHS), another highly heritable sleep disorder 16 , conducted in a Japanese population 17 . They identified genome-wide significance in single nucleotide polymorphism (SNP) on the CRAT gene located in 9q34.11 17 .…”

Section: Introductionmentioning

confidence: 99%

“…We also conducted a polygenic risk analysis of ADHD traits using a summary from the previous GWAS study of essential hypersomnia (EHS), another highly heritable sleep disorder 16 , conducted in a Japanese population 17 . They identified genome-wide significance in single nucleotide polymorphism (SNP) on the CRAT gene located in 9q34.11 17 . Although there has been no direct evidence showing the high-concordance rate in twins and familial accumulation of EHS and narcolepsy, it has been reported that these disorders share several susceptibility genes 16 , and~40% of the heritability of EHS was explained by the genetic background of narcolepsy 12 .…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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Attention deficit hyperactive disorder (ADHD) is a highly heritable neurodevelopmental disorder, and excessive daytime sleepiness is frequently observed in ADHD patients. Excessive daytime sleepiness is also a core symptom of narcolepsy and essential hypersomnia (EHS), which are also heritable conditions. Psychostimulants are effective for the symptomatic control of ADHD (primary recommended intervention) and the two sleep disorders (frequent off-label use). However, the common biological mechanism for these disorders has not been well understood. Using a previously collected genome-wide association study of narcolepsy and EHS, we calculated polygenic risk scores (PRS) for each individual. We investigated a possible genetic association between ADHD and narcolepsy traits in the Hamamatsu Birth Cohort for mothers and children (HBC study) (n = 876). Gene-set enrichment analyses were used to identify common pathways underlying these disorders. Narcolepsy PRS were significantly associated with ADHD traits both in the hyperactivity domain (e.g., P-value threshold < 0.05, β [SE], 5.815 [1.774]; P = 0.002) and inattention domain (e.g., P-value threshold < 0.05, β [SE], 5.734 [1.761]; P = 0.004). However, EHS PRS was not significantly associated with either domain of ADHD traits. Gene-set enrichment analyses revealed that pathways related to dopaminergic signaling, immune systems, iron metabolism, and glial cell function involved in both ADHD and narcolepsy. Findings indicate that ADHD and narcolepsy are genetically related, and there are possible common underlying biological mechanisms for this relationship. Future studies replicating these findings would be warranted to elucidate the genetic vulnerability for daytime sleepiness in individuals with ADHD.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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

Tanida

Shimada

Khor

et al. 2021

Sleep Biol. Rhythms

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Genetics of narcolepsy

Miyagawa

Tokunaga

2019

Hum Genome Var

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Narcolepsy is a term that was initially coined by Gélineáu in 1880 and is a chronic neurological sleep disorder that manifests as a difficulty in maintaining wakefulness and sleep for long periods. Currently, narcolepsy is subdivided into two types according to the International Classification of Sleep Disorders, 3rd edition: narcolepsy type 1 (NT1) and narcolepsy type 2 (NT2). NT1 is characterized by excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis and is caused by a marked reduction in neurons in the hypothalamus that produce orexin (hypocretin), which is a wakefulness-associated neuropeptide. Except for cataplexy, NT2 exhibits most of the same symptoms as NT1. NT1 is a multifactorial disease, and genetic variations at multiple loci are associated with NT1. Almost all patients with NT1 carry the specific human leukocyte antigen (HLA) allele HLA-DQB1*06:02. Genome-wide association studies have uncovered >10 genomic variations associated with NT1. Rare variants associated with NT1 have also been identified by DNA genome sequencing. NT2 is also a complex disorder, but its underlying genetic architecture is poorly understood. However, several studies have revealed loci that increase susceptibility to NT2. The currently identified loci cannot explain the heritability of narcolepsy (NT1 and NT2). We expect that future genomic research will provide important contributions to our understanding of the genetic basis and pathogenesis of narcolepsy.

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A variant at 9q34.11 is associated with HLA-DQB1*06:02 negative essential hypersomnia

Cited by 5 publications

References 41 publications

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

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

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

Genetics of narcolepsy

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