Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy

Hor, Hyun; Kutalik, Zoltán; Dauvilliers, Yves; Valsesia, Armand; Lammers, Gert Jan; Donjacour, Claire E H M; Iranzo, Álex; Santamaría, Joan; Peraita-Adrados, Rosa; Vicário, José L.; Overeem, Sebastiaan; Arnulf, Isabelle; Théodorou, Ioannis; Jennum, Poul; Knudsen, Stine; Bassetti, Claudio; Mathis, Johannes; Lecendreux, Michel; Mayer, Geert; Geisler, Peter; Benetó, A; Petit, Brice; Pfister, Corinne; Bürki, Julie Vienne; Didelot, Gérard; Billiard, Michel; Ercilla, Guadalupe; Verduijn, Willem; Claas, Frans H.J.; Vollenweider, Péter; Waeber, Gérard; Waterworth, Dawn; Mooser, Vincent; Heinzer, Raphaël; Beckmann, Jacques S.; Bergmann, Sven; Tafti, Mehdi

doi:10.1038/ng.647

Cited by 175 publications

(110 citation statements)

References 25 publications

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“…This has raised considerable interest across disciplines, from immunology and genetics, to medicine and evolutionary biology. Remarkable recent advances in our understanding of the genetic basis of common diseases have been achieved by genome-wide association studies (GWAS) (Wellcome Trust Case Control Consortium 2007;Manolio 2010), which have confirmed the preeminence of the MHC in terms of the magnitude of effect, statistical confidence, and the number of associations with autoimmune, infectious, and inflammatory diseases, together with cancer and adverse drug effects (Conde et al 2010;Hamza et al 2010;Hor et al 2010;Singer et al 2010).…”

mentioning

confidence: 99%

Pervasive haplotypic variation in the spliceo-transcriptome of the human major histocompatibility complex

Vandiedonck¹,

Taylor²,

Lockstone³

et al. 2011

Genome Res.

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The human major histocompatibility complex (MHC) on chromosome 6p21 is a paradigm for genomics, showing remarkable polymorphism and striking association with immune and non-immune diseases. The complex genomic landscape of the MHC, notably strong linkage disequilibrium, has made resolving causal variants very challenging. A promising approach is to investigate gene expression levels considered as tractable intermediate phenotypes in mapping complex diseases. However, how transcription varies across the MHC, notably relative to specific haplotypes, remains unknown. Here, using an original hybrid tiling and splice junction microarray that includes alternate allele probes, we draw the first high-resolution strand-specific transcription map for three common MHC haplotypes (HLA-A1-B8-Cw7-DR3, HLA-A3-B7-Cw7-DR15, and HLA-A26-B18-Cw5-DR3-DQ2) strongly associated with autoimmune diseases including type 1 diabetes, systemic lupus erythematosus, and multiple sclerosis. We find that haplotype-specific differences in gene expression are common across the MHC, affecting 96 genes (46.4%), most significantly the zing finger protein gene ZFP57. Differentially expressed probes are correlated with polymorphisms between haplotypes, consistent with cis effects that we directly demonstrate for ZFP57 in a cohort of healthy volunteers (P = 1.2 3 10 -14 ). We establish that alternative splicing is significantly more frequent in the MHC than genome-wide (72.5% vs. 62.1% of genes, P # 1 3 10 -4 ) and shows marked haplotypic differences. We also unmask novel and abundant intergenic transcription involving 31% of transcribed blocks identified. Our study reveals that the renowned MHC polymorphism also manifests as transcript diversity, and our novel haplotype-based approach marks a new step toward identification of regulatory variants involved in the control of MHCassociated phenotypes and diseases.

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mentioning

confidence: 99%

Pervasive haplotypic variation in the spliceo-transcriptome of the human major histocompatibility complex

Vandiedonck¹,

Taylor²,

Lockstone³

et al. 2011

Genome Res.

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“…While there is a growing interest in identifying the genetic basis of insomnia, the mechanisms are not well substantiated compared with that of other sleep disorders, such as narcolepsy 30,31 or restless leg syndrome. 32,33 Using genetic strategies such as candidate Exposed = a relative of a case affected with insomnia; Unexposed = a relative of a control not suffering from insomnia.…”

Section: Discussionmentioning

confidence: 99%

Familial Aggregation of Insomnia

Jarrin

Morin

Rochefort

et al. 2016

Sleep

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Study Objectives: There is little information about familial aggregation of insomnia; however, this type of information is important to (1) improve our understanding of insomnia risk factors and (2) to design more effective treatment and prevention programs. This study aimed to investigate evidence of familial aggregation of insomnia among first-degree relatives of probands with and without insomnia. Methods: Cases (n = 134) and controls (n = 145) enrolled in a larger epidemiological study were solicited to invite their first-degree relatives and spouses to complete a standardized sleep/insomnia survey. In total, 371 first-degree relatives (M age = 51.9 years, SD = 18.0; 34.3% male) and 138 spouses (M age = 55.5 years, SD = 12.2; 68.1% male) completed the survey assessing the nature, severity, and frequency of sleep disturbances. The dependent variable was insomnia in first-degree relatives and spouses. Familial aggregation was claimed if the risk of insomnia was significantly higher in the exposed (relatives of cases) compared to the unexposed cohort (relatives of controls). The risk of insomnia was also compared between spouses in the exposed (spouses of cases) and unexposed cohort (spouses of controls). Results: The risk of insomnia in exposed and unexposed biological relatives was 18.6% and 10.4%, respectively, yielding a relative risk (RR) of 1.80 (p = .04) after controlling for age and sex. The risk of insomnia in exposed and unexposed spouses was 9.1% and 4.2%, respectively; however, corresponding RR of 2.13 (p = .28) did not differ significantly. Conclusions: Results demonstrate evidence of strong familial aggregation of insomnia. Additional research is warranted to further clarify and disentangle the relative contribution of genetic and environmental factors in insomnia.

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“…Zukünftige genomweite Assoziationsstudien (GWAS) könnten auf diese Fragen Antworten geben, wie es für andere Schlafstörungen bereits möglich war (z. B. Narkolepsie [25,26,27] und Restless-Legs-Syndrome [28]). Für die einzelnen genetisch bedingten Parkinson-Syndrome ist bereits für einige Formen auch eine Assoziation mit einem RBD in Segregation mit entsprechenden Mutationen vermutet worden.…”

Section: Andere Genetische Parkinson-syndrome Und Rbdunclassified

Genetische Aspekte der REM-Schlaf-Verhaltensstörung

Young

2014

Somnologie

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Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy

Cited by 175 publications

References 25 publications

Pervasive haplotypic variation in the spliceo-transcriptome of the human major histocompatibility complex

Pervasive haplotypic variation in the spliceo-transcriptome of the human major histocompatibility complex

Familial Aggregation of Insomnia

Genetische Aspekte der REM-Schlaf-Verhaltensstörung

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