Biological and clinical insights from genetics of insomnia symptoms

Lane, Jacqueline M.; Jones, Samuel E.; Dashti, Hassan S.; Wood, Andrew R.; Aragam, Krishna; Hees, Vincent T. van; Strand, Linn Beate; Winsvold, Bendik S.; Wang, Heming; Bowden, Jack; Song, Yanwei; Patel, Krunal; Anderson, Simon; Beaumont, Robin N; Bechtold, David A.; Cade, Brian E.; Haas, Mary E.; Kathiresan, Sekar; Little, Max A.; Luik, Annemarie I.; Loudon, A. S. I.; Purcell, Shaun; Richmond, Rebecca C; Scheer, Frank A.J.L.; Schormair, Barbara; Tyrrell, Jessica; Winkelman, John W.; Winkelmann, Juliane; Sleep, Hunt All In; Hveem, Kristian; Zhao, Chen; Nielsen, Jonas B.; Willer, Cristen J.; Redline, Susan; Spiegelhalder, Kai; Kyle, Simon D.; Ray, David; Zwart, John‐Anker; Brumpton, Ben; Frayling, Timothy M.; Lawlor, Debbie A.; Rutter, Martin K.; Weedon, Michael N.; Saxena, Richa

doi:10.1038/s41588-019-0361-7

Cited by 303 publications

(318 citation statements)

References 59 publications

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“…We performed a follow-up sensitivity GWAS for snoring including BMI as a covariate to explore the effects of BMI on associated variants. The results revealed 97 genome-wide significant SNPs across 34 genomic risk loci ( Figure 2) with overall SNP heritability on the liability 16 , RNA5SP471 16,17 and SND1 and NSUN3, previously associated with alcohol consumption; 14,[16][17][18] FTO and SND1, associated with coffee consumption; 19 LMO4 associated with insomnia; 20 and RNA5SP471 with narcolepsy. 20,21 Also, ROBO2, previously associated with chronotype; 22,23 and multiple genes (DLEU7, MSRB3, FTO, ANAPC4, SMG6, SND1, SIM1, KCNQ5, CEP120, MACF1, SNAP91 and BCL2) previously associated with musculoskeletal traits such as height and heel bone mineral density (Supplementary File 1 and Supplementary File 2).…”

Section: Sensitivity Analysismentioning

confidence: 99%

“…The results revealed 97 genome-wide significant SNPs across 34 genomic risk loci ( Figure 2) with overall SNP heritability on the liability 16 , RNA5SP471 16,17 and SND1 and NSUN3, previously associated with alcohol consumption; 14,[16][17][18] FTO and SND1, associated with coffee consumption; 19 LMO4 associated with insomnia; 20 and RNA5SP471 with narcolepsy. 20,21 Also, ROBO2, previously associated with chronotype; 22,23 and multiple genes (DLEU7, MSRB3, FTO, ANAPC4, SMG6, SND1, SIM1, KCNQ5, CEP120, MACF1, SNAP91 and BCL2) previously associated with musculoskeletal traits such as height and heel bone mineral density (Supplementary File 1 and Supplementary File 2). [24][25][26][27] Genome-wide gene-based association analysis identified 179 genes associated with snoring beyond genome wide significance (p<2.636e-6; bonferroni corrected threshold for 18,971 tested genes) several of which were consistent with the mapped genes.…”

Section: Sensitivity Analysismentioning

confidence: 99%

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Insights into the aetiology of snoring from observational and genetic investigations in the UK Biobank (n=408,317)

Campos

García-Marín

Byrne

et al. 2019

Preprint

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We conducted the largest study of snoring using data from the UK Biobank (n ~ 408,000; snorers ~152,000). A genome-wide association study (GWAS) identified 42 genome-wide significant loci, with a SNP-based heritability estimate of ~10% on the liability scale. Genetic correlations with body mass index, alcohol intake, smoking, schizophrenia, anorexia nervosa and neuroticism were observed. Gene-based associations identified 173 genes, including DLEU7, MSRB3 and POC5 highlighting genes expressed in brain, cerebellum, lungs, blood, and oesophagus tissues. We used polygenic scores (PGS) to predict recent snoring and probable obstructive sleep apnoea (OSA) in an independent Australian sample (n~8,000). Mendelian randomisation analyses provided evidence that larger whole body fat mass causes snoring. Altogether, our results uncover new insights into the aetiology of snoring as a complex sleep-related trait and its role in health and disease beyond being a cardinal symptom of OSA.

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Section: Sensitivity Analysismentioning

confidence: 99%

Section: Sensitivity Analysismentioning

confidence: 99%

Insights into the aetiology of snoring from observational and genetic investigations in the UK Biobank (n=408,317)

Campos

García-Marín

Byrne

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…We have successfully used large-scale human cohorts, such as the UK Biobank, to explore connections between measures of circadian strain (shiftwork, chronotype, and sleep) and prevalent disease (32,40,41). Low prevalence diseases such as pulmonary fibrosis present unique challenges.…”

Section: Analysis Of Reverbα Gene Targets Revealed Striking Enrichmenmentioning

confidence: 99%

The circadian clock protein REVERBα inhibits pulmonary fibrosis development

Cunningham¹,

Meijer²,

Nazgiewicz³

et al. 2019

Preprint

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Pulmonary inflammatory responses lie under circadian control; however the importance of circadian mechanisms in fibrosis is not understood. Here, we identify a striking change to these mechanisms resulting in a gain of amplitude and lack of synchrony within pulmonary fibrotic tissue. These changes result from an infiltration of mesenchymal cells, an important cell type in the pathogenesis of pulmonary fibrosis. Mutation of the core clock protein REVERBα in these cells exacerbated the development of bleomycin-induced fibrosis, whereas mutation of REVERBα in club or myeloid cells had no effect on the bleomycin phenotype. Knockdown of REVERBα revealed regulation of the poorly described transcription factor TBPL1. Both REVERBα and TBPL1 altered integrinβ1 focal adhesion formation, resulting in increased myofibroblast activation. The translational importance of our findings was established through analysis of two human cohorts. In the UK Biobank circadian strain markers (sleep length, chronotype and shift work) are associated with pulmonary fibrosis making them novel risk factors. In a separate cohort REVERBα expression was increased in human idiopathic pulmonary fibrosis (IPF) lung tissue. Pharmacological targeting of REVERBα inhibited myofibroblast activation in IPF fibroblasts and collagen secretion in organotypic cultures from IPF patients, suggesting targeting REVERBα could be a viable therapeutic approach.SignificanceThe circadian clock plays an essential role in energy metabolism, and inflammation. In contrast the importance of the clock in the pathogenesis of fibrosis remains poorly explored. This study describes a striking alteration in circadian biology during pulmonary fibrosis where the relatively arrhythmic alveolar structures gain circadian but desynchronous rhythmicity due to infiltration by fibroblasts. Disruption of the clock in these cells, which are not widely implicated in circadian pathophysiology, results in a pro-fibrotic phenotype. Translation of these findings in humans revealed previously unrecognised important circadian risk factors for pulmonary fibrosis (sleep length, chronotype and shift work). In addition, targeting REVERBα repressed collagen secretion from human fibrotic lung tissue making this protein a promising therapeutic target.

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“…Genome-wide association analysis was performed using a linear regression under an additive model in PLINK v1.9 (16,17) using Ricopili (https://sites.google.com/a/broadinstitute.org/ricopili/). Age, gender, and ten principal components 8 were included as covariates. For subsequent gene-based analyses, SNPs with an INFO score ≥0.8 and MAF ≥0.01 were included.…”

Section: Gwas Of Adhd Symptom Scores In the Nijmegen Biomedical Studymentioning

confidence: 99%

“…In addition, circadian genes and circuits have been implicated, as ADHD often goes together with sleep disturbances, and abnormal circadian rhythms of melatonin secretion have been observed in children and adult patients with ADHD (7). Importantly, positive genetic correlations between insomnia and sleep-related traits and ADHD exist (8). Moreover, disrupting the activity of the circadian clock gene Per1 in both mice and zebrafish revealed ADHD-like symptoms (9).…”

Section: Introductionmentioning

confidence: 99%