Genome-wide association analyses of chronotype in 697,828 individuals provides insights into circadian rhythms

Jones, Samuel E.; Lane, Jacqueline M.; Wood, Andrew R.; Hees, Vincent T. van; Tyrrell, Jessica; Beaumont, Robin N; Jeffries, Aaron R.; Dashti, Hassan S.; Hillsdon, Melvyn; Ruth, Katherine S.; Tuke, Marcus A.; Yaghootkar, Hanieh; Sharp, Seth A.; Jie, Yingjie; Thompson, William E.; Harrison, Jamie; Dawes, Amy; Byrne, Enda M.; Tiemeier, Henning; Allebrandt, Karla V.; Bowden, Jack; Ray, David; Freathy, Rachel M.; Murray, Anna; Mazzotti, Diego R.; Gehrman, Philip; Lawlor, Debbie A.; Frayling, Timothy M.; Rutter, Martin K.; Hinds, David A.; Saxena, Richa; Weedon, Michael N.

doi:10.1038/s41467-018-08259-7

Cited by 523 publications

(584 citation statements)

References 90 publications

(113 reference statements)

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“…Nonetheless, this group highlights enrichments that may warrant further exploration. The observation that data corresponding to the "morning person" trait reveals enrichment within the blue cone open chromatin region (OCR) profile ( Figure 3A) is consistent with the finding that genes expressed highly in retinal tissue are enriched in "morning person" loci (Jones et al 2019), adding evidence to a potential biological relationship. Additionally, the observed enrichment for astrocyte OCR profile with body mass index heritability ( Figure 3A) mirrors mounting evidence that astrocytes and other glia play a role in controlling body weight (García-Cáceres et al 2012).…”

Section: Mouse-derived Human Profiles Recapitulate Cell Population DIsupporting

confidence: 77%

Leveraging mouse chromatin data for heritability enrichment informs common disease architecture and reveals cortical layer contributions to schizophrenia

Hook

McCallion

2018

Preprint

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Genome-wide association studies have implicated thousands of non-coding variants across human phenotypes. However, they cannot directly inform the cellular context in which disease-associated variants act. Here, we use open chromatin profiles from discrete mouse cell populations to address this challenge. We applied stratified linkage disequilibrium score regression and evaluated heritability enrichment in 64 genome-wide association studies, emphasizing schizophrenia. We provide evidence that mouse-derived human open chromatin profiles can serve as powerful proxies for difficult to obtain human cell populations, facilitating the illumination of common disease heritability enrichment across an array of human phenotypes. We demonstrate signatures from discrete subpopulations of cortical excitatory and inhibitory neurons are significantly enriched for schizophrenia heritability with maximal enrichment in discrete cortical layer V excitatory neurons. We also show differences between schizophrenia and bipolar disorder are concentrated in excitatory neurons in layers II-III, IV, V as well as the dentate gyrus. Finally, we use these data to fine-map variants in 177 schizophrenia loci, nominating variants in 104/177 loci, and place them in the cellular context where they may modulate risk.

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Section: Mouse-derived Human Profiles Recapitulate Cell Population DIsupporting

confidence: 77%

Leveraging mouse chromatin data for heritability enrichment informs common disease architecture and reveals cortical layer contributions to schizophrenia

Hook

McCallion

2018

Preprint

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“…This locus is significant in Gut microbiome composition [Davenport et al, ], Preschool internalizing problems [Benke et al, ], Educational attainment (MTAG) [Lee et al, ], Chronotype [Jones et al, ] in GWAS study…”

Section: Discussionmentioning

confidence: 99%

“…Locus and supporting evidence Gene function a KCNMB2 chr3:178276488-178562217 This locus is significant in schizophrenia and bipolar disorder [Bergen et al, 2012]; Amyotrophic lateral sclerosis [Xie et al, 2014]; Hippocampal sclerosis [Beecham et al, 2014]; Suicide attempts [Kimbrel et al, 2018];Recurrent major depressive disorder [Hall et al, 2018] [Herold et al, 2016]; Psychosis [Ikeda et al, 2013]; Neuroticism ; Response to anti-depressant treatment in major depressive ; Schizophrenia [Sullivan et al, 2008];Loneliness [Gao et al, 2017] Lee et al, 2018] in GWAS study. Two de novo and rare variants in SNX29 have been reported in autism [Iossifov et al, 2014;RK et al, 2017] [Davenport et al, 2015], Preschool internalizing problems [Benke et al, 2014], Educational attainment (MTAG) [Lee et al, 2018], Chronotype [Jones et al, 2019] in GWAS study PCSK2, Proprotein Convertase Subtilisin/Kexin type 2 Involved in the processing of hormone and other protein precursors at sites comprised of pairs of basic amino acid residues. Responsible for the release of glucagon from proglucagon in pancreatic A cells EEF1A2 chr20:62119367-62130436 This locus is significant in autism spectrum disorder or schizophrenia in the GWAS study [Autism Spectrum Disorders Working Group of The Psychiatric Genomics, 2017].…”

Section: Genementioning

confidence: 99%

Genome‐wide association analysis of autism identified multiple loci that have been reported as strong signals for neuropsychiatric disorders

et al. 2019

Autism Research

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Autism is a common neurodevelopmental disorder with a moderate to a high degree of heritability, but only a few common genetic variants that explain the heritability have been associated. We performed a genome‐wide transmission disequilibrium test analysis of a newly genotyped autism case–parent triad samples (127 trios) in Han Chinese, identified top association signals at multiple single nucleotide polymorphisms (SNPs), including rs9839376 (OR = 2.59, P = 1.27 × 10−05) at KCNMB2, rs6044680 (OR = 0.319, P = 4.82 × 10−05) and rs7274133 (OR = 0.313, P = 3.22 × 10−05) at PCSK2, and rs310619 (OR = 2.40, P = 7.44 × 10−05) at EEF1A2. Furthermore, a genome‐wide combined P‐value of individual SNPs in two independent case–parent triad samples (total 402 triads, n = 1,206) identified SNPs at EGFLAM, ZDHHC2, AGBL1, and SNX29 as additional association signals for autism. While none of these signals achieved a genome‐wide significance in the two samples of our study, they have been reported in a previous genome‐wide association study of neuropsychiatric disorders, and the majority of these SNP have a significant cis‐regulatory association with mRNA in human tissues (false discovery rate (FDR) < 0.05). Our study warrants further study or replication with additional sample for association with autism and other neuropsychiatric disorders. Autism Res 2020, 13: 382–396. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary Autism is a common neurodevelopmental disorder, heritable, but only a few common genetic variants that explain the heritability have been associated. We conducted a genome‐wide association study with two cohorts of autism case–parent triad samples in Han Chinese and identified multiple single nucleotide polymorphisms that were reported as strong association signals in a previous genome‐wide association study of other neuropsychiatric disorders or related traits. Our study provides evidence for shared genetic variants among autism and other neuropsychiatric disorders.

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“…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 analyses of chronotype in 697,828 individuals provides insights into circadian rhythms

Cited by 523 publications

References 90 publications

Leveraging mouse chromatin data for heritability enrichment informs common disease architecture and reveals cortical layer contributions to schizophrenia

Leveraging mouse chromatin data for heritability enrichment informs common disease architecture and reveals cortical layer contributions to schizophrenia

Genome‐wide association analysis of autism identified multiple loci that have been reported as strong signals for neuropsychiatric disorders

The circadian clock protein REVERBα inhibits pulmonary fibrosis development

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