Evaluation of polygenic risks for narcolepsy and essential hypersomnia

Yamasaki, Makari; Miyagawa, Taku; Toyoda, Hiromi; Khor, Seik‐Soon; Liu, Xiaoxi; Kuwabara, Hitoshi; Kano, Yukiko; Shimada, Takafumi; Sugiyama, Toshiro; Nishida, Hisami; Sugaya, Nagisa; Tochigi, Mamoru; Otowa, Takeshi; Okazaki, Yuji; Kaiya, Hisanobu; Kawamura, Yoshiya; Miyashita, Akinori; Kuwano, Ryozo; Kasai, Kiyoto; Tanii, Hisashi; Sasaki, Tsukasa; Honda, Yoshiyuki; Honda, Masashi; Tokunaga, Katsushi

doi:10.1038/jhg.2016.65

Cited by 19 publications

(13 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For autoimmune diseases with a main association signal coming from HLA class II region, such as type 1 diabetes, celiac disease, multiple sclerosis, SLE, inflammatory bowel disease, and narcolepsy, the reported variance explained by HLA alleles varies from 2% to 58%. 52,53 In this study, rs4642516 (the top SNP in HLA region) explained 9.7% (Nagelkerke's pseudo-R 2 ) of the disease variance in Japanese childhood SSNS. Considering the complicated LD structure within the HLA region, there may be strong intercorrelations between the index SNP in GWAS and the two independent classic HLA alleles (rs4642516 and HLA-DRB1*08:02, r 2 =0.02, D'=1; rs4642516 and HLA-DQB1*06:04, r 2 =0.21, D'=1 in combined dataset).…”

Section: Discussionmentioning

confidence: 57%

Strong Association of the HLA-DR/DQ Locus with Childhood Steroid-Sensitive Nephrotic Syndrome in the Japanese Population

Jia

Horinouchi

Hitomi

et al. 2018

JASN

Self Cite

View full text Add to dashboard Cite

Nephrotic syndrome is the most common cause of chronic glomerular disease in children. Most of these patients develop steroid-sensitive nephrotic syndrome (SSNS), but the loci conferring susceptibility to childhood SSNS are mainly unknown. We conducted a genome-wide association study (GWAS) in the Japanese population; 224 patients with childhood SSNS and 419 adult healthy controls were genotyped using the Affymetrix Japonica Array in the discovery stage. Imputation for six genes (, ,, , and) was conducted on the basis of Japanese-specific references. We performed genotyping for /- using a sequence-specific oligonucleotide-probing method on a Luminex platform. Whole-genome imputation was conducted using a phased reference panel of 2049 healthy Japanese individuals. Replication was performed in an independent Japanese sample set including 216 patients and 719 healthy controls. We genotyped candidate single-nucleotide polymorphisms using the DigiTag2 assay. The most significant association was detected in the region and replicated (rs4642516 [minor allele G], combined=7.84×10; odds ratio [OR], 0.33; 95% confidence interval [95% CI], 0.26 to 0.41; rs3134996 [minor allele A], combined =1.72×10; OR, 0.29; 95% CI, 0.23 to 0.37). (=1.82×10; OR, 2.62; 95% CI, 1.94 to 3.54) and (=2.09×10; OR, 0.10; 95% CI, 0.05 to 0.21) were considered primary alleles associated with childhood SSNS. (=7.01×10; OR, 3.60; 95% CI, 2.46 to 5.29) was identified as the most significant genetic susceptibility factor. The most significant association with childhood SSNS was detected in the region. Further allele/haplotype analyses should enhance our understanding of molecular mechanisms underlying SSNS.

show abstract

Section: Discussionmentioning

confidence: 57%

Strong Association of the HLA-DR/DQ Locus with Childhood Steroid-Sensitive Nephrotic Syndrome in the Japanese Population

Jia

Horinouchi

Hitomi

et al. 2018

JASN

Self Cite

View full text Add to dashboard Cite

show abstract

“…Narcolepsy is strongly associated with HLA DQB1*06:02, and genome-wide association studies have identified polymorphisms in the T-cell-receptor-α (TCRA) locus on chromosome 14, TNFSF4 (also called OX40L), Cathepsin H (CTSH) the purinergic receptor P2RY11, the DNA methyltransferase DNMT1, and carnitine palmitoyltransferase (CPT1B) 12–14. TCRA encodes the α chain of the α β-heterodimer of the T-cell receptor on CD4 + T-helper cells and CD8 + T-cytotoxic cells 15.…”

Section: Pathophysiology and Geneticsmentioning

confidence: 99%

New developments in the management of narcolepsy

Abad

Guilleminault

2017

NSS

View full text Add to dashboard Cite

Narcolepsy is a life-long, underrecognized sleep disorder that affects 0.02%–0.18% of the US and Western European populations. Genetic predisposition is suspected because of narcolepsy’s strong association with HLA DQB1*06-02, and genome-wide association studies have identified polymorphisms in T-cell receptor loci. Narcolepsy pathophysiology is linked to loss of signaling by hypocretin-producing neurons; an autoimmune etiology possibly triggered by some environmental agent may precipitate hypocretin neuronal loss. Current treatment modalities alleviate the main symptoms of excessive daytime somnolence (EDS) and cataplexy and, to a lesser extent, reduce nocturnal sleep disruption, hypnagogic hallucinations, and sleep paralysis. Sodium oxybate (SXB), a sodium salt of γ hydroxybutyric acid, is a first-line agent for cataplexy and EDS and may help sleep disruption, hypnagogic hallucinations, and sleep paralysis. Various antidepressant medications including norepinephrine serotonin reuptake inhibitors, selective serotonin reuptake inhibitors, and tricyclic antidepressants are second-line agents for treating cataplexy. In addition to SXB, modafinil and armodafinil are first-line agents to treat EDS. Second-line agents for EDS are stimulants such as methylphenidate and extended-release amphetamines. Emerging therapies include non-hypocretin-based therapy, hypocretin-based treatments, and immunotherapy to prevent hypocretin neuronal death. Non-hypocretin-based novel treatments for narcolepsy include pitolisant (BF2.649, tiprolisant); JZP-110 (ADX-N05) for EDS in adults; JZP 13-005 for children; JZP-386, a deuterated sodium oxybate oral suspension; FT 218 an extended-release formulation of SXB; and JNJ-17216498, a new formulation of modafinil. Clinical trials are investigating efficacy and safety of SXB, modafinil, and armodafinil in children. γ-amino butyric acid (GABA) modulation with GABAA receptor agonists clarithromycin and flumazenil may help daytime somnolence. Other drugs investigated include GABAB agonists (baclofen), melanin-concentrating hormone antagonist, and thyrotropin-releasing hormone agonists. Hypocretin-based therapies include hypocretin peptide replacement administered either through an intracerebroventricular route or intranasal route. Hypocretin neuronal transplant and transforming stem cells into hypothalamic neurons are also discussed in this article. Immunotherapy to prevent hypocretin neuronal death is reviewed.

show abstract

“…One recent study conducted in Japan demonstrated that the relative risk of narcolepsy in affected first-degree family members is 10-to 40-fold higher than in the general population, suggesting that genetic factors play an important role in this disease 12 . Of note, the HLA DQB1*15:01 and DQB1*06:02 genes have been shown to be associated with narcolepsy, and additional genes may be involved 13 .…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Evaluation of polygenic risks for narcolepsy and essential hypersomnia

Cited by 19 publications

References 48 publications

Strong Association of the HLA-DR/DQ Locus with Childhood Steroid-Sensitive Nephrotic Syndrome in the Japanese Population

Strong Association of the HLA-DR/DQ Locus with Childhood Steroid-Sensitive Nephrotic Syndrome in the Japanese Population

New developments in the management of narcolepsy

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

Contact Info

Product

Resources

About