Genome-wide meta-analysis of insomnia prioritizes genes associated with metabolic and psychiatric pathways

  • Roth, T. Insomnia: definition, prevalence, etiology, and consquences. J. Clin. Sleep Med. 3, S7–S10 (2007).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Kripke, D. F., Garfinkel, L., Wingard, D. L., Klauber, M. R. & Marler, M. R. Mortality associated with sleep duration and insomnia. Arch. Gen. Psychiatry 59, 131–136 (2002).

    PubMed 
    Article 

    Google Scholar 

  • Daley, M., Morin, C. M., Leblanc, M., Grégoire, J. & Savard, J. The economic burden of insomnia: direct and indirect costs for individuals with insomnia. Sleep 32, 55–64 (2009).

    PubMed 
    Article 
    PubMed Central 

    Google Scholar 

  • Lind, M. J., Aggen, S. H., Kirkpatrick, R. M., Kendler, K. S. & Amstadter, A. B. A longitudinal twin study of insomnia symptoms in adults. Sleep 38, 1423–1430 (2015).

    PubMed 
    Article 
    PubMed Central 

    Google Scholar 

  • Jansen, P. R. et al. Genome-wide analysis of insomnia in 1,331,010 individuals identifies new risk loci and functional pathways. Nat. Genet. 51, 394–403 (2019).

    CAS 
    PubMed 
    Article 

    Google Scholar 

  • Lane, J. M. et al. Genome-wide association analyses of sleep disturbance traits identify new loci and highlight shared genetics with neuropsychiatric and metabolic traits. Nat. Genet. 49, 274–281 (2017).

    CAS 
    PubMed 
    Article 

    Google Scholar 

  • Lane, J. M. et al. Biological and clinical insights from genetics of insomnia symptoms. Nat. Genet. 51, 387–393 (2019).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar 

  • Watanabe, K. et al. A global overview of pleiotropy and genetic architecture in complex traits. Nat. Genet. 51, 1339–1348 (2019).

    CAS 
    PubMed 
    Article 

    Google Scholar 

  • Zaitlen, N., Paşaniuc, B., Gur, T., Ziv, E. & Halperin, E. Leveraging genetic variability across populations for the identification of causal variants. Am. J. Hum. Genet. 86, 23–33 (2010).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar 

  • Findlay, G. M. et al. Accurate classification of BRCA1 variants with saturation genome editing. Nature 562, 217–222 (2018).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar 

  • Hammerschlag, A. R. et al. Genome-wide association analysis of insomnia complaints identifies risk genes and genetic overlap with psychiatric and metabolic traits. Nat. Genet. 49, 1584–1592 (2017).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar 

  • Willer, C. J., Li, Y. & Abecasis, G. R. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26, 2190–2191 (2010).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar 

  • Bulik-sullivan, B. K. et al. LD score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat. Genet. 47, 291–295 (2015).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar 

  • Finucane, H. K. et al. Partitioning heritability by functional annotation using genome-wide association summary statistics. Nat. Genet. 47, 1228–1235 (2015).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar 

  • Schormair, B. et al. Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry: a meta-analysis. Lancet Neurol. 16, 898–907 (2017).

    PubMed 
    Article 
    PubMed Central 

    Google Scholar 

  • Tsai, F. J. et al. A genome-wide association study identifies susceptibility variants for type 2 diabetes in Han Chinese. PLoS Genet. 6, e1000847 (2010).

    PubMed 
    Article 
    CAS 
    PubMed Central 

    Google Scholar 

  • Schunkert, H. et al. Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nat. Genet. 43, 333–340 (2011).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar 

  • Koido, K. et al. Associations between LSAMP gene polymorphisms and major depressive disorder and panic disorder. Transl. Psychiatry 2, e152 (2012).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar 

  • Must, A. et al. Association of limbic system-associated membrane protein (LSAMP) to male completed suicide. BMC Med. Genet. 9, 34 (2008).

    PubMed 
    Article 
    CAS 
    PubMed Central 

    Google Scholar 

  • Watanabe, K., Taskesen, E., van Bochoven, A. & Posthuma, D. Functional mapping and annotation of genetic associations with FUMA. Nat. Commun. 8, 1826 (2017).

    PubMed 
    Article 
    CAS 
    PubMed Central 

    Google Scholar 

  • de Leeuw, C. A., Mooij, J. M., Heskes, T. & Posthuma, D. MAGMA: generalized gene-set analysis of GWAS data. PLoS Comput. Biol. 11, e1004219 (2015).

    PubMed 
    Article 
    CAS 
    PubMed Central 

    Google Scholar 

  • Kichaev, G. et al. Integrating functional data to prioritize causal variants in statistical fine-mapping studies. PLoS Genet. 10, 2–3 (2014).

    Article 
    CAS 

    Google Scholar 

  • Benner, C. et al. FINEMAP: efficient variable selection using summary data from genome-wide association studies. Bioinformatics 32, 1493–1501 (2016).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar 

  • Schaid, D. J., Chen, W. & Larson, N. B. From genome-wide associations to candidate causal variants by statistical fine-mapping. Nat. Rev. Genet. 19, 491–504 (2018).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar 

  • Weissbrod, O. et al. Functionally informed fine-mapping and polygenic localization of complex trait heritability. Nat. Genet. 52, 1355–1363 (2020).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar 

  • The GTEx Consortium. The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science 369, 1318–1330 (2020).

    Article 
    CAS 
    PubMed Central 

    Google Scholar 

  • Wang, D. et al. Comprehensive functional genomic resource and integrative model for the human brain. Science 362, eaat8464 (2018).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar 

  • Võsa, U. et al. Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression. Nat. Genet. 53, 1300–1310 (2021).

    PubMed 
    Article 
    CAS 
    PubMed Central 

    Google Scholar 

  • Li, T. et al. A scored human protein-protein interaction network to catalyze genomic interpretation. Nat. Methods 14, 61–64 (2016).

    PubMed 
    Article 
    CAS 
    PubMed Central 

    Google Scholar 

  • Sinnott-Armstrong, N., Naqvi, S., Rivas, M. & Pritchard, J. K. GWAS of three molecular traits highlights core genes and pathways alongside a highly polygenic background. eLife 10, e58615 (2021).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar 

  • Locke, A. E. et al. Genetic studies of body mass index yield new insights for obesity biology. Nature 518, 197–206 (2015).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar 

  • Wray, N. R. et al. Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression. Nat. Genet. 50, 668–681 (2018).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar 

  • Savage, J. E. et al. GWAS meta-analysis (N=279,930) identifies new genes and functional links to intelligence. Nat. Genet. 50, 912–919 (2018).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar 

  • Lee, J. J. et al. Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals. Nat. Genet. 50, 1112–1121 (2018).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar 

  • Singh, K. et al. Neuronal growth and behavioral alterations in mice deficient for the psychiatric disease-associated negr1 gene. Front. Mol. Neurosci. 11, 30 (2018).

    PubMed 
    Article 
    CAS 
    PubMed Central 

    Google Scholar 

  • Singh, K. et al. Neural cell adhesion molecule Negr1 deficiency in mouse results in structural brain endophenotypes and behavioral deviations related to psychiatric disorders. Sci. Rep. 9, 5457 (2019).

    PubMed 
    Article 
    CAS 
    PubMed Central 

    Google Scholar 

  • Koike, N. et al. Transcriptional architecture and chromatin landscape of the core circadian clock in mammals. Science 338, 349–354 (2012).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar 

  • Bonnet, M. H. & Arand, D. L. Hyperarousal and insomnia: state of the science. Sleep Med. Rev. 14, 9–15 (2010).

    PubMed 
    Article 

    Google Scholar 

  • Hikosaka, O. The habenula: from stress evasion to value-based decision-making. Nat. Rev. Neurosci. 11, 503–513 (2010).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar 

  • Benarroch, E. E. Habenula: recently recognized functions and potential clinical relevance. Neurology 58, 992–1000 (2015).

    Article 

    Google Scholar 

  • Zhao, H. & Rusak, B. Circadian firing-rate rhythms and light responses of rat habenular nucleus neurons in vivo and in vitro. Neuroscience 132, 519–528 (2005).

    CAS 
    PubMed 
    Article 

    Google Scholar 

  • Haun, F., Eckenrode, T. C. & Murray, M. Habenula and thalamus cell transplants restore normal sleep behaviors disrupted by denervation of the interpeduncular nucleus. J. Neurosci. 12, 3282–3290 (1992).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar 

  • Bianco, I. H. & Wilson, S. W. The habenular nuclei: a conserved asymmetric relay station in the vertebrate brain. Philos. Trans. R. Soc. B Biol. Sci. 364, 1005–1020 (2009).

    Article 

    Google Scholar 

  • Chrobok, L. et al. Intrinsic circadian timekeeping properties of the thalamic lateral geniculate nucleus. J. Neurosci. Res. 99, 3306–3324 (2021).

    CAS 
    PubMed 
    Article 

    Google Scholar 

  • Harrington, M. E. The ventral lateral geniculate nucleus and the intergeniculate leaflet: interrelated structures in the visual and circadian systems. Neurosci. Biobehav. Rev. 21, 705–727 (1997).

    CAS 
    PubMed 
    Article 

    Google Scholar 

  • Johnson, R. F., Moore, R. Y. & Morin, L. P. Lateral geniculate lesions alter circadian activity rhythms in the hamster. Brain Res. Bull. 22, 411–422 (1989).

    CAS 
    PubMed 
    Article 

    Google Scholar 

  • Moore, R. Y. & Speh, J. C. GABA is the principal neurotransmitter of the circadian system. Neurosci. Lett. 150, 112–116 (1993).

    CAS 
    PubMed 
    Article 

    Google Scholar 

  • Melzer, S. & Monyer, H. Diversity and function of corticopetal and corticofugal GABAergic projection neurons. Nat. Rev. Neurosci. 21, 499–515 (2020).

    CAS 
    PubMed 
    Article 

    Google Scholar 

  • España, R. A. & Scammell, T. E. Sleep neurobiology from a clinical perspective. Sleep 34, 845–858 (2011).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Gottesmann, C. GABA mechanisms and sleep. Neuroscience 111, 231–239 (2002).

    CAS 
    PubMed 
    Article 

    Google Scholar 

  • Kostin, A., Alam, M. A., McGinty, D. & Alam, M. N. Adult hypothalamic neurogenesis and sleep-wake dysfunction in aging. Sleep 44, zsaa173 (2021).

    PubMed 
    Article 

    Google Scholar 

  • Levenson, J. C., Kay, D. B. & Buysse, D. J. The pathophysiology of insomnia. Chest 147, 1179–1192 (2015).

    PubMed 
    Article 
    PubMed Central 

    Google Scholar 

  • Spiegelhalder, K. et al. Neuroimaging insights into insomnia. Curr. Neurol. Neurosci. Rep. 15, 9 (2015).

    PubMed 
    Article 
    CAS 

    Google Scholar 

  • Kay, D. B. & Buysse, D. J. Hyperarousal and beyond: new insights to the pathophysiology of insomnia disorder through functional neuroimaging studies. Brain Sci. 7, brainsci7030023 (2017).

    Article 
    CAS 

    Google Scholar 

  • Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar 

  • Abraham, G., Qiu, Y. & Inouye, M. FlashPCA2: principal component analysis of Biobank-scale genotype datasets. Bioinformatics 33, 2776–2778 (2017).

    CAS 
    PubMed 
    Article 

    Google Scholar 

  • Zhu, Z. et al. Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets. Nat. Genet. 48, 481–487 (2016).

    CAS 
    PubMed 
    Article 

    Google Scholar 

  • Euesden, J., Lewis, C. M. & Reilly, P. F. O. PRSice: Polygenic Risk Score software. Bioinformatics 31, 1466–1468 (2015).

  • Hawrylycz, M. J. et al. An anatomically comprehensive atlas of the adult human brain transcriptome. Nature 489, 391–399 (2012).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar 

  • Zeisel, A. et al. Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq. Science 348, 1138–1142 (2015).

    Article 
    CAS 

    Google Scholar 

  • Romanov, R. A. et al. Molecular interrogation of hypothalamic organization reveals distinct dopamine neuronal subtypes. Nat. Neurosci. 20, 176–188 (2017).

    CAS 
    PubMed 
    Article 

    Google Scholar 

  • Marques, S. et al. Oligodendrocyte heterogneity in the mouse juvenile and adult central nervous system. Science 352, 1326–1329 (2016).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar 

  • La Manno, G. et al. Molecular diversity of midbrain development in mouse, human, and stem cells. Cell 167, 566–580 (2016).

    PubMed 
    Article 
    CAS 
    PubMed Central 

    Google Scholar 

  • Muñoz-Manchado, A. B. et al. Diversity of interneurons in the dorsal atriatum revealed by single-cell RNA sequencing and PatchSeq. Cell Rep. 24, 2179–2190 (2018).

    PubMed 
    Article 
    CAS 
    PubMed Central 

    Google Scholar 

  • Saunders, A. et al. Molecular diversity and specializations among the cells of the adult mouse brain. Cell 174, 1015–1030 (2018).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar 

  • Watanabe, K., Umićević Mirkov, M., de Leeuw, C. A., van den Heuvel, M. P. & Posthuma, D. Genetic mapping of cell type specificity for complex traits. Nat. Commun. 10, 3222 (2019).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar 

  • Liberzon, A. et al. Molecular signatures database (MSigDB) 3.0. Bioinformatics 27, 1739–1740 (2011).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar 

  • Benner, C. et al. Prospects of fine-mapping trait-associated genomic regions by using summary statistics from genome-wide association studies. Am. J. Hum. Genet. 101, 539–551 (2017).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar 

  • Wang, K., Li, M. & Hakonarson, H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 38, e164 (2010).

    PubMed 
    Article 
    CAS 
    PubMed Central 

    Google Scholar 

  • Kircher, M. et al. A general framework for estimating the relative pathogenicity of human genetic variants. Nat. Genet. 46, 310–315 (2014).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar 

  • Boyle, A. P. et al. Annotation of functional variation in personal genomes using RegulomeDB. Genome Res. 22, 1790–1797 (2012).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar 

  • Roadmap Epigenomics Consortium. Integrative analysis of 111 reference human epigenomes. Nature 518, 317–330 (2015).

    Article 
    CAS 
    PubMed Central 

    Google Scholar 

  • Ernst, J. & Kellis, M. ChromHMM: automating chromatin-state discovery and characterization. Nat. Methods 9, 215–216 (2012).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar 

  • Giambartolomei, C. et al. Bayesian test for colocalisation between pairs of genetic association studies using summary statistics. PLoS Genet. 10, e1004383 (2014).

    PubMed 
    Article 
    CAS 
    PubMed Central 

    Google Scholar 

  • Schmitt, A. D. et al. A Compendium of chromatin contact maps reveals spatially active regions in the human genome. Cell Rep. 17, 2042–2059 (2016).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar 

  • Maaten, L. VanDer & Hinton, G. Visualizing high dimensional data using t-SNE. J. Mach. Learn. Res. 9, 2579–2605 (2008).

    Google Scholar 

  • Watanabe, K. Gene prioritization using multi-loci information for insomnia meta analysis. https://doi.org/10.5281/zenodo.6598552

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