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

23Andme Research Team

doi:10.1038/s41588-022-01124-w

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

23Andme Research Team

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Abstract

Insomnia is a heritable, highly prevalent sleep disorder for which no sufficient treatment currently exists. Previous genome-wide association studies with up to 1.3 million subjects identified over 200 associated loci. This extreme polygenicity suggested that many more loci remain to be discovered. The current study almost doubled the sample size to 593,724 cases and 1,771,286 controls, thereby increasing statistical power, and identified 554 risk loci (including 364 novel loci). To capitalize on this large number of loci, we propose a novel strategy to prioritize genes using external biological resources and functional interactions between genes across risk loci. Of all 3,898 genes naively implicated from the risk loci, we prioritize 289 and find brain-tissue expression specificity and enrichment in specific gene sets of synaptic signaling functions and neuronal differentiation. We show that this novel gene prioritization strategy yields specific hypotheses on underlying mechanisms of insomnia that would have been missed by traditional approaches.

Original language	English
Pages (from-to)	1125-1132
Number of pages	8
Journal	Nature genetics
Volume	54
Issue number	8
Early online date	14 Jul 2022
DOIs	https://doi.org/10.1038/s41588-022-01124-w
Publication status	Published - Aug 2022

Bibliographical note

Funding Information:
We thank both UKB and 23andMe participants who consented to participate in research, and researchers who collected and contributed the data. D.P. was funded by The Netherlands Organization for Scientific Research (no. NWO VICI 453-14-005), NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (grant no. 024.004.012) and a European Research Council advanced grant (no. ERC-2018-AdG GWAS2FUNC 834057). E.J.W.V.S. was funded by the European Research Council (no. ERC-ADG-2014-671084 INSOMNIA) and P.R.J. was funded by the Netherlands Organization for Scientific Research (no. ZonMW VENI-09150162010138). The research was conducted using the UK Biobank Resource (application no. 16406). Analyses were carried out on the Genetic Cluster Computer hosted by the Dutch National Computing and Networking Services, SurfSARA. We additionally thank the GTEx Portal for providing RNA-seq data. The research was based in part on data from the Million Veteran Program – Office of Research and Development, Veterans Health Administration, supported by award nos. CSP 575B and Merit 1I01CX001849.e.

Funding Information:
We thank both UKB and 23andMe participants who consented to participate in research, and researchers who collected and contributed the data. D.P. was funded by The Netherlands Organization for Scientific Research (no. NWO VICI 453-14-005), NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (grant no. 024.004.012) and a European Research Council advanced grant (no. ERC-2018-AdG GWAS2FUNC 834057). E.J.W.V.S. was funded by the European Research Council (no. ERC-ADG-2014-671084 INSOMNIA) and P.R.J. was funded by the Netherlands Organization for Scientific Research (no. ZonMW VENI-09150162010138). The research was conducted using the UK Biobank Resource (application no. 16406). Analyses were carried out on the Genetic Cluster Computer hosted by the Dutch National Computing and Networking Services, SurfSARA. We additionally thank the GTEx Portal for providing RNA-seq data. The research was based in part on data from the Million Veteran Program – Office of Research and Development, Veterans Health Administration, supported by award nos. CSP 575B and Merit 1I01CX001849.e.

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.

Funding

We thank both UKB and 23andMe participants who consented to participate in research, and researchers who collected and contributed the data. D.P. was funded by The Netherlands Organization for Scientific Research (no. NWO VICI 453-14-005), NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (grant no. 024.004.012) and a European Research Council advanced grant (no. ERC-2018-AdG GWAS2FUNC 834057). E.J.W.V.S. was funded by the European Research Council (no. ERC-ADG-2014-671084 INSOMNIA) and P.R.J. was funded by the Netherlands Organization for Scientific Research (no. ZonMW VENI-09150162010138). The research was conducted using the UK Biobank Resource (application no. 16406). Analyses were carried out on the Genetic Cluster Computer hosted by the Dutch National Computing and Networking Services, SurfSARA. We additionally thank the GTEx Portal for providing RNA-seq data. The research was based in part on data from the Million Veteran Program – Office of Research and Development, Veterans Health Administration, supported by award nos. CSP 575B and Merit 1I01CX001849.e. We thank both UKB and 23andMe participants who consented to participate in research, and researchers who collected and contributed the data. D.P. was funded by The Netherlands Organization for Scientific Research (no. NWO VICI 453-14-005), NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (grant no. 024.004.012) and a European Research Council advanced grant (no. ERC-2018-AdG GWAS2FUNC 834057). E.J.W.V.S. was funded by the European Research Council (no. ERC-ADG-2014-671084 INSOMNIA) and P.R.J. was funded by the Netherlands Organization for Scientific Research (no. ZonMW VENI-09150162010138). The research was conducted using the UK Biobank Resource (application no. 16406). Analyses were carried out on the Genetic Cluster Computer hosted by the Dutch National Computing and Networking Services, SurfSARA. We additionally thank the GTEx Portal for providing RNA-seq data. The research was based in part on data from the Million Veteran Program – Office of Research and Development, Veterans Health Administration, supported by award nos. CSP 575B and Merit 1I01CX001849.e.

Funders	Funder number
Dutch National Computing and Networking Services
GTEx
Million Veteran Program
Office of Research and Development
Health Services Research and Development	1I01CX001849, CSP 575B
Health Services Research and Development
European Research Council	ERC-2018-AdG GWAS2FUNC 834057, VENI-09150162010138, ERC-ADG-2014-671084, 16406
European Research Council
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	024.004.012, NWO VICI 453-14-005
Nederlandse Organisatie voor Wetenschappelijk Onderzoek

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41588-022-01124-w

Genome-wide meta-analysis of insomnia prioritizes genes associated with metabolic and psychiatric pathwaysFinal published version, 3.96 MBLicence: Article 25fa Dutch Copyright Act

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@article{6a3605c1ab4a495296aaaa28cd11159d,

title = "Genome-wide meta-analysis of insomnia prioritizes genes associated with metabolic and psychiatric pathways",

abstract = "Insomnia is a heritable, highly prevalent sleep disorder for which no sufficient treatment currently exists. Previous genome-wide association studies with up to 1.3 million subjects identified over 200 associated loci. This extreme polygenicity suggested that many more loci remain to be discovered. The current study almost doubled the sample size to 593,724 cases and 1,771,286 controls, thereby increasing statistical power, and identified 554 risk loci (including 364 novel loci). To capitalize on this large number of loci, we propose a novel strategy to prioritize genes using external biological resources and functional interactions between genes across risk loci. Of all 3,898 genes naively implicated from the risk loci, we prioritize 289 and find brain-tissue expression specificity and enrichment in specific gene sets of synaptic signaling functions and neuronal differentiation. We show that this novel gene prioritization strategy yields specific hypotheses on underlying mechanisms of insomnia that would have been missed by traditional approaches.",

author = "Kyoko Watanabe and Jansen, {Philip R.} and Savage, {Jeanne E.} and Priyanka Nandakumar and Xin Wang and Michelle Agee and Stella Aslibekyan and Adam Auton and Bell, {Robert K.} and Katarzyna Bryc and Clark, {Sarah K.} and Elson, {Sarah L.} and Kipper Fletez-Brant and Pierre Fontanillas and Furlotte, {Nicholas A.} and Gandhi, {Pooja M.} and Karl Heilbron and Barry Hicks and Huber, {Karen E.} and Jewett, {Ethan M.} and Yunxuan Jiang and Aaron Kleinman and Lin, {Keng Han} and Litterman, {Nadia K.} and McCreight, {Jennifer C.} and McIntyre, {Matthew H.} and McManus, {Kimberly F.} and Mountain, {Joanna L.} and Mozaffari, {Sahar V.} and Noblin, {Elizabeth S.} and Northover, {Carrie A.M.} and Jared O{\textquoteright}Connell and Pitts, {Steven J.} and Poznik, {G. David} and Sathirapongsasuti, {J. Fah} and Shelton, {Janie F.} and Jing Shi and Suyash Shringarpure and Chao Tian and Tung, {Joyce Y.} and Tunney, {Robert J.} and Vladimir Vacic and Wei Wang and Hinds, {David A.} and Joel Gelernter and Levey, {Daniel F.} and Renato Polimanti and Stein, {Murray B.} and {Van Someren}, {Eus J.W.} and Smit, {August B.} and Danielle Posthuma and {23Andme Research Team}",

note = "Funding Information: We thank both UKB and 23andMe participants who consented to participate in research, and researchers who collected and contributed the data. D.P. was funded by The Netherlands Organization for Scientific Research (no. NWO VICI 453-14-005), NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (grant no. 024.004.012) and a European Research Council advanced grant (no. ERC-2018-AdG GWAS2FUNC 834057). E.J.W.V.S. was funded by the European Research Council (no. ERC-ADG-2014-671084 INSOMNIA) and P.R.J. was funded by the Netherlands Organization for Scientific Research (no. ZonMW VENI-09150162010138). The research was conducted using the UK Biobank Resource (application no. 16406). Analyses were carried out on the Genetic Cluster Computer hosted by the Dutch National Computing and Networking Services, SurfSARA. We additionally thank the GTEx Portal for providing RNA-seq data. The research was based in part on data from the Million Veteran Program – Office of Research and Development, Veterans Health Administration, supported by award nos. CSP 575B and Merit 1I01CX001849.e. Funding Information: We thank both UKB and 23andMe participants who consented to participate in research, and researchers who collected and contributed the data. D.P. was funded by The Netherlands Organization for Scientific Research (no. NWO VICI 453-14-005), NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (grant no. 024.004.012) and a European Research Council advanced grant (no. ERC-2018-AdG GWAS2FUNC 834057). E.J.W.V.S. was funded by the European Research Council (no. ERC-ADG-2014-671084 INSOMNIA) and P.R.J. was funded by the Netherlands Organization for Scientific Research (no. ZonMW VENI-09150162010138). The research was conducted using the UK Biobank Resource (application no. 16406). Analyses were carried out on the Genetic Cluster Computer hosted by the Dutch National Computing and Networking Services, SurfSARA. We additionally thank the GTEx Portal for providing RNA-seq data. The research was based in part on data from the Million Veteran Program – Office of Research and Development, Veterans Health Administration, supported by award nos. CSP 575B and Merit 1I01CX001849.e. Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2022",

month = aug,

doi = "10.1038/s41588-022-01124-w",

language = "English",

volume = "54",

pages = "1125--1132",

journal = "Nature genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "8",

}

TY - JOUR

T1 - Genome-wide meta-analysis of insomnia prioritizes genes associated with metabolic and psychiatric pathways

AU - Watanabe, Kyoko

AU - Jansen, Philip R.

AU - Savage, Jeanne E.

AU - Nandakumar, Priyanka

AU - Wang, Xin

AU - Agee, Michelle

AU - Aslibekyan, Stella

AU - Auton, Adam

AU - Bell, Robert K.

AU - Bryc, Katarzyna

AU - Clark, Sarah K.

AU - Elson, Sarah L.

AU - Fletez-Brant, Kipper

AU - Fontanillas, Pierre

AU - Furlotte, Nicholas A.

AU - Gandhi, Pooja M.

AU - Heilbron, Karl

AU - Hicks, Barry

AU - Huber, Karen E.

AU - Jewett, Ethan M.

AU - Jiang, Yunxuan

AU - Kleinman, Aaron

AU - Lin, Keng Han

AU - Litterman, Nadia K.

AU - McCreight, Jennifer C.

AU - McIntyre, Matthew H.

AU - McManus, Kimberly F.

AU - Mountain, Joanna L.

AU - Mozaffari, Sahar V.

AU - Noblin, Elizabeth S.

AU - Northover, Carrie A.M.

AU - O’Connell, Jared

AU - Pitts, Steven J.

AU - Poznik, G. David

AU - Sathirapongsasuti, J. Fah

AU - Shelton, Janie F.

AU - Shi, Jing

AU - Shringarpure, Suyash

AU - Tian, Chao

AU - Tung, Joyce Y.

AU - Tunney, Robert J.

AU - Vacic, Vladimir

AU - Wang, Wei

AU - Hinds, David A.

AU - Gelernter, Joel

AU - Levey, Daniel F.

AU - Polimanti, Renato

AU - Stein, Murray B.

AU - Van Someren, Eus J.W.

AU - Smit, August B.

AU - Posthuma, Danielle

AU - 23Andme Research Team

N1 - Funding Information: We thank both UKB and 23andMe participants who consented to participate in research, and researchers who collected and contributed the data. D.P. was funded by The Netherlands Organization for Scientific Research (no. NWO VICI 453-14-005), NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (grant no. 024.004.012) and a European Research Council advanced grant (no. ERC-2018-AdG GWAS2FUNC 834057). E.J.W.V.S. was funded by the European Research Council (no. ERC-ADG-2014-671084 INSOMNIA) and P.R.J. was funded by the Netherlands Organization for Scientific Research (no. ZonMW VENI-09150162010138). The research was conducted using the UK Biobank Resource (application no. 16406). Analyses were carried out on the Genetic Cluster Computer hosted by the Dutch National Computing and Networking Services, SurfSARA. We additionally thank the GTEx Portal for providing RNA-seq data. The research was based in part on data from the Million Veteran Program – Office of Research and Development, Veterans Health Administration, supported by award nos. CSP 575B and Merit 1I01CX001849.e. Funding Information: We thank both UKB and 23andMe participants who consented to participate in research, and researchers who collected and contributed the data. D.P. was funded by The Netherlands Organization for Scientific Research (no. NWO VICI 453-14-005), NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (grant no. 024.004.012) and a European Research Council advanced grant (no. ERC-2018-AdG GWAS2FUNC 834057). E.J.W.V.S. was funded by the European Research Council (no. ERC-ADG-2014-671084 INSOMNIA) and P.R.J. was funded by the Netherlands Organization for Scientific Research (no. ZonMW VENI-09150162010138). The research was conducted using the UK Biobank Resource (application no. 16406). Analyses were carried out on the Genetic Cluster Computer hosted by the Dutch National Computing and Networking Services, SurfSARA. We additionally thank the GTEx Portal for providing RNA-seq data. The research was based in part on data from the Million Veteran Program – Office of Research and Development, Veterans Health Administration, supported by award nos. CSP 575B and Merit 1I01CX001849.e. Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.

PY - 2022/8

Y1 - 2022/8

N2 - Insomnia is a heritable, highly prevalent sleep disorder for which no sufficient treatment currently exists. Previous genome-wide association studies with up to 1.3 million subjects identified over 200 associated loci. This extreme polygenicity suggested that many more loci remain to be discovered. The current study almost doubled the sample size to 593,724 cases and 1,771,286 controls, thereby increasing statistical power, and identified 554 risk loci (including 364 novel loci). To capitalize on this large number of loci, we propose a novel strategy to prioritize genes using external biological resources and functional interactions between genes across risk loci. Of all 3,898 genes naively implicated from the risk loci, we prioritize 289 and find brain-tissue expression specificity and enrichment in specific gene sets of synaptic signaling functions and neuronal differentiation. We show that this novel gene prioritization strategy yields specific hypotheses on underlying mechanisms of insomnia that would have been missed by traditional approaches.

AB - Insomnia is a heritable, highly prevalent sleep disorder for which no sufficient treatment currently exists. Previous genome-wide association studies with up to 1.3 million subjects identified over 200 associated loci. This extreme polygenicity suggested that many more loci remain to be discovered. The current study almost doubled the sample size to 593,724 cases and 1,771,286 controls, thereby increasing statistical power, and identified 554 risk loci (including 364 novel loci). To capitalize on this large number of loci, we propose a novel strategy to prioritize genes using external biological resources and functional interactions between genes across risk loci. Of all 3,898 genes naively implicated from the risk loci, we prioritize 289 and find brain-tissue expression specificity and enrichment in specific gene sets of synaptic signaling functions and neuronal differentiation. We show that this novel gene prioritization strategy yields specific hypotheses on underlying mechanisms of insomnia that would have been missed by traditional approaches.

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JF - Nature genetics

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ER -

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

Abstract

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