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Genome-wide Analysis of Insomnia (N=1,331,010) Identifies Novel Loci and Functional Pathways

Philip R. Jansen, Kyoko Watanabe, Sven Stringer, Nathan Skene, Julien Bryois, Anke R. Hammerschlag, Christiaan A. de Leeuw, Jeroen Benjamins, Ana B. Muñoz-Manchado, Mats Nagel, Jeanne E. Savage, Henning Tiemeier, Tonya White, Joyce Y. Tung, David A. Hinds, Vladimir Vacic, Patrick F. Sullivan, Sophie van der Sluis, Tinca J.C. Polderman, August B. Smit, Jens Hjerling-Leffler, Eus J.W. Van Someren, Danielle Posthuma
doi: https://doi.org/10.1101/214973
Philip R. Jansen
1 Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University Amsterdam, The Netherlands
2 Department of Child and Adolescent Psychiatry, Erasmus University Medical Center, Rotterdam, the Netherlands
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Kyoko Watanabe
1 Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University Amsterdam, The Netherlands
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Sven Stringer
1 Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University Amsterdam, The Netherlands
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Nathan Skene
3 Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
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Julien Bryois
4 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
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Anke R. Hammerschlag
1 Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University Amsterdam, The Netherlands
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Christiaan A. de Leeuw
1 Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University Amsterdam, The Netherlands
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Jeroen Benjamins
5 Departments of Social, Health and Organizational Psychology, and of Experimental Psychology, Utrecht University, the Netherlands
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Ana B. Muñoz-Manchado
3 Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
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Mats Nagel
1 Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University Amsterdam, The Netherlands
6 Department of Clinical Genetics, Section Complex Trait Genetics, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, the Netherlands
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Jeanne E. Savage
1 Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University Amsterdam, The Netherlands
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Henning Tiemeier
2 Department of Child and Adolescent Psychiatry, Erasmus University Medical Center, Rotterdam, the Netherlands
7 Department of Psychiatry, Erasmus University Medical Center, Rotterdam, the Netherlands
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Tonya White
2 Department of Child and Adolescent Psychiatry, Erasmus University Medical Center, Rotterdam, the Netherlands
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Joyce Y. Tung
8 23andMe, Inc., Mountain View, CA, USA
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David A. Hinds
8 23andMe, Inc., Mountain View, CA, USA
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Vladimir Vacic
8 23andMe, Inc., Mountain View, CA, USA
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Patrick F. Sullivan
4 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
9 Department of Genetics, University of North Carolina, Chapel Hill, USA
10 Department of Psychiatry, University of North Carolina, Chapel Hill, USA
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Sophie van der Sluis
1 Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University Amsterdam, The Netherlands
6 Department of Clinical Genetics, Section Complex Trait Genetics, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, the Netherlands
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Tinca J.C. Polderman
1 Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University Amsterdam, The Netherlands
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August B. Smit
11 Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University Amsterdam, Amsterdam, Netherlands
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Jens Hjerling-Leffler
3 Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
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Eus J.W. Van Someren
12 Departments of Integrative Neurophysiology and Psychiatry InGeest, Amsterdam Neuroscience, VU University and Medical Center, Amsterdam, The Netherlands
13 Department of Sleep and Cognition, Netherlands Institute for Neuroscience, an institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands
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Danielle Posthuma
1 Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University Amsterdam, The Netherlands
6 Department of Clinical Genetics, Section Complex Trait Genetics, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, the Netherlands
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  • For correspondence: d.posthuma@vu.nl
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Abstract

Insomnia is the second-most prevalent mental disorder, with no sufficient treatment available. Despite a substantial role of genetic factors, only a handful of genes have been implicated and insight into the associated neurobiological pathways remains limited. Here, we use an unprecedented large genetic association sample (N=1,331,010) to allow detection of a substantial number of genetic variants and gain insight into biological functions, cell types and tissues involved in insomnia. We identify 202 genome-wide significant loci implicating 956 genes through positional, eQTL and chromatin interaction mapping. We show involvement of the axonal part of neurons, of specific cortical and subcortical tissues, and of two specific cell-types in insomnia: striatal medium spiny neurons and hypothalamic neurons. These cell-types have been implicated previously in the regulation of reward processing, sleep and arousal in animal studies, but have never been genetically linked to insomnia in humans. We found weak genetic correlations with other sleep-related traits, but strong genetic correlations with psychiatric and metabolic traits. Mendelian randomization identified causal effects of insomnia on specific psychiatric and metabolic traits. Our findings reveal key brain areas and cells implicated in the neurobiology of insomnia and its related disorders, and provide novel targets for treatment.

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Posted January 30, 2018.
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Genome-wide Analysis of Insomnia (N=1,331,010) Identifies Novel Loci and Functional Pathways
Philip R. Jansen, Kyoko Watanabe, Sven Stringer, Nathan Skene, Julien Bryois, Anke R. Hammerschlag, Christiaan A. de Leeuw, Jeroen Benjamins, Ana B. Muñoz-Manchado, Mats Nagel, Jeanne E. Savage, Henning Tiemeier, Tonya White, Joyce Y. Tung, David A. Hinds, Vladimir Vacic, Patrick F. Sullivan, Sophie van der Sluis, Tinca J.C. Polderman, August B. Smit, Jens Hjerling-Leffler, Eus J.W. Van Someren, Danielle Posthuma
bioRxiv 214973; doi: https://doi.org/10.1101/214973
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Genome-wide Analysis of Insomnia (N=1,331,010) Identifies Novel Loci and Functional Pathways
Philip R. Jansen, Kyoko Watanabe, Sven Stringer, Nathan Skene, Julien Bryois, Anke R. Hammerschlag, Christiaan A. de Leeuw, Jeroen Benjamins, Ana B. Muñoz-Manchado, Mats Nagel, Jeanne E. Savage, Henning Tiemeier, Tonya White, Joyce Y. Tung, David A. Hinds, Vladimir Vacic, Patrick F. Sullivan, Sophie van der Sluis, Tinca J.C. Polderman, August B. Smit, Jens Hjerling-Leffler, Eus J.W. Van Someren, Danielle Posthuma
bioRxiv 214973; doi: https://doi.org/10.1101/214973

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