A genome-wide meta-analysis uncovers six sequence variants conferring risk of vertigo

Astros Th Skuladottir; Gyda Bjornsdottir; Muhammad Sulaman Nawaz; Hannes Petersen; Solvi Rognvaldsson; Kristjan Helgi Swerford Moore; Pall I. Olafsson; Sigurður H. Magnusson; Anna Bjornsdottir; Olafur A. Sveinsson; Gudrun R. Sigurdardottir; Sædís Sævarsdóttir; Erna V. Ivarsdottir; Lilja Stefánsdóttir; Bjarni Gunnarsson; Joseph B. Muhlestein; Kirk U. Knowlton; David A. Jones; Lincoln D. Nadauld; Annette M. Hartmann; Dan Rujescu; Michael Strupp; Guðmundur Bragi Walters; Thorgeir E. Thorgeirsson; Ingileif Jónsdóttir; Hilma Holm; Gudmar Thorleifsson; Daniel F. Gudbjartsson; Patrick Sulem; Hreinn Stefansson; Kari Stefansson

doi:10.1038/s42003-021-02673-2

A genome-wide meta-analysis uncovers six sequence variants conferring risk of vertigo

Astros Th Skuladottir^*, Gyda Bjornsdottir, Muhammad Sulaman Nawaz, Hannes Petersen, Solvi Rognvaldsson, Kristjan Helgi Swerford Moore, Pall I. Olafsson, Sigurður H. Magnusson, Anna Bjornsdottir, Olafur A. Sveinsson, Gudrun R. Sigurdardottir, Sædís Sævarsdóttir, Erna V. Ivarsdottir, Lilja Stefánsdóttir, Bjarni Gunnarsson, Joseph B. Muhlestein, Kirk U. Knowlton, David A. Jones, Lincoln D. Nadauld, Annette M. HartmannDan Rujescu, Michael Strupp, Guðmundur Bragi Walters, Thorgeir E. Thorgeirsson, Ingileif Jónsdóttir, Hilma Holm, Gudmar Thorleifsson, Daniel F. Gudbjartsson, Patrick Sulem, Hreinn Stefansson, Kari Stefansson

^*Corresponding author for this work

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Abstract

Vertigo is the leading symptom of vestibular disorders and a major risk factor for falls. In a genome-wide association study of vertigo (N_cases = 48,072, N_controls = 894,541), we uncovered an association with six common sequence variants in individuals of European ancestry, including missense variants in ZNF91, OTOG, OTOGL, and TECTA, and a cis-eQTL for ARMC9. The association of variants in ZNF91, OTOGL, and OTOP1 was driven by an association with benign paroxysmal positional vertigo. Using previous reports of sequence variants associating with age-related hearing impairment and motion sickness, we found eight additional variants that associate with vertigo. Although disorders of the auditory and the vestibular system may co-occur, none of the six genome-wide significant vertigo variants were associated with hearing loss and only one was associated with age-related hearing impairment. Our results uncovered sequence variants associating with vertigo in a genome-wide association study and implicated genes with known roles in inner ear development, maintenance, and disease.

Original language	English
Article number	1148
Pages (from-to)	1148
Journal	Communications Biology
Volume	4
Issue number	1
DOIs	https://doi.org/10.1038/s42003-021-02673-2
Publication status	Published - 7 Oct 2021

Bibliographical note

Funding Information:
We thank the participants in this study for their valuable contribution to research. We also thank our colleagues at deCODE who contributed to genotyping and analysis of the WGS data. This research was conducted using the UK Biobank Resource (application number 24898). We acknowledge Stacey Knight, Tyler Barker, Jeffrey L. Anderson, and John F. Carlquist for their contribution to the HerediGene: Population study. We acknowledge the participants and investigators of the FinnGen study. The financial support from the European Commission to the NeuroPain project (FP7#HEALTH-2013-602891-2) and painFACT project (H2020-2020-848099), and the National Institutes of Health (R01DE022905) is acknowledged.

Publisher Copyright:
© 2021, The Author(s).

Other keywords

Ear, Inner/growth & development
Genome, Human
Genome-Wide Association Study
Humans
Labyrinth Diseases/genetics
Mutation, Missense
Vertigo/genetics

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s42003-021-02673-2Final published version, 1.55 MBLicence: CC BY

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Skuladottir, A. T., Bjornsdottir, G., Nawaz, M. S., Petersen, H., Rognvaldsson, S., Moore, K. H. S., Olafsson, P. I., Magnusson, S. H., Bjornsdottir, A., Sveinsson, O. A., Sigurdardottir, G. R., Sævarsdóttir, S., Ivarsdottir, E. V., Stefánsdóttir, L., Gunnarsson, B., Muhlestein, J. B., Knowlton, K. U., Jones, D. A., Nadauld, L. D., ... Stefansson, K. (2021). A genome-wide meta-analysis uncovers six sequence variants conferring risk of vertigo. Communications Biology, 4(1), 1148. [1148]. https://doi.org/10.1038/s42003-021-02673-2

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abstract = "Vertigo is the leading symptom of vestibular disorders and a major risk factor for falls. In a genome-wide association study of vertigo (Ncases = 48,072, Ncontrols = 894,541), we uncovered an association with six common sequence variants in individuals of European ancestry, including missense variants in ZNF91, OTOG, OTOGL, and TECTA, and a cis-eQTL for ARMC9. The association of variants in ZNF91, OTOGL, and OTOP1 was driven by an association with benign paroxysmal positional vertigo. Using previous reports of sequence variants associating with age-related hearing impairment and motion sickness, we found eight additional variants that associate with vertigo. Although disorders of the auditory and the vestibular system may co-occur, none of the six genome-wide significant vertigo variants were associated with hearing loss and only one was associated with age-related hearing impairment. Our results uncovered sequence variants associating with vertigo in a genome-wide association study and implicated genes with known roles in inner ear development, maintenance, and disease.",

keywords = "Ear, Inner/growth & development, Genome, Human, Genome-Wide Association Study, Humans, Labyrinth Diseases/genetics, Mutation, Missense, Vertigo/genetics",

author = "Skuladottir, {Astros Th} and Gyda Bjornsdottir and Nawaz, {Muhammad Sulaman} and Hannes Petersen and Solvi Rognvaldsson and Moore, {Kristjan Helgi Swerford} and Olafsson, {Pall I.} and Magnusson, {Sigur{\dh}ur H.} and Anna Bjornsdottir and Sveinsson, {Olafur A.} and Sigurdardottir, {Gudrun R.} and S{\ae}d{\'i}s S{\ae}varsd{\'o}ttir and Ivarsdottir, {Erna V.} and Lilja Stef{\'a}nsd{\'o}ttir and Bjarni Gunnarsson and Muhlestein, {Joseph B.} and Knowlton, {Kirk U.} and Jones, {David A.} and Nadauld, {Lincoln D.} and Hartmann, {Annette M.} and Dan Rujescu and Michael Strupp and Walters, {Gu{\dh}mundur Bragi} and Thorgeirsson, {Thorgeir E.} and Ingileif J{\'o}nsd{\'o}ttir and Hilma Holm and Gudmar Thorleifsson and Gudbjartsson, {Daniel F.} and Patrick Sulem and Hreinn Stefansson and Kari Stefansson",

note = "Funding Information: We thank the participants in this study for their valuable contribution to research. We also thank our colleagues at deCODE who contributed to genotyping and analysis of the WGS data. This research was conducted using the UK Biobank Resource (application number 24898). We acknowledge Stacey Knight, Tyler Barker, Jeffrey L. Anderson, and John F. Carlquist for their contribution to the HerediGene: Population study. We acknowledge the participants and investigators of the FinnGen study. The financial support from the European Commission to the NeuroPain project (FP7#HEALTH-2013-602891-2) and painFACT project (H2020-2020-848099), and the National Institutes of Health (R01DE022905) is acknowledged. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

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Skuladottir, AT, Bjornsdottir, G, Nawaz, MS, Petersen, H, Rognvaldsson, S, Moore, KHS, Olafsson, PI, Magnusson, SH, Bjornsdottir, A, Sveinsson, OA, Sigurdardottir, GR, Sævarsdóttir, S, Ivarsdottir, EV, Stefánsdóttir, L, Gunnarsson, B, Muhlestein, JB, Knowlton, KU, Jones, DA, Nadauld, LD, Hartmann, AM, Rujescu, D, Strupp, M, Walters, GB, Thorgeirsson, TE, Jónsdóttir, I, Holm, H, Thorleifsson, G, Gudbjartsson, DF, Sulem, P, Stefansson, H & Stefansson, K 2021, 'A genome-wide meta-analysis uncovers six sequence variants conferring risk of vertigo', Communications Biology, vol. 4, no. 1, 1148, pp. 1148. https://doi.org/10.1038/s42003-021-02673-2

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T1 - A genome-wide meta-analysis uncovers six sequence variants conferring risk of vertigo

AU - Skuladottir, Astros Th

AU - Bjornsdottir, Gyda

AU - Nawaz, Muhammad Sulaman

AU - Petersen, Hannes

AU - Rognvaldsson, Solvi

AU - Moore, Kristjan Helgi Swerford

AU - Olafsson, Pall I.

AU - Magnusson, Sigurður H.

AU - Bjornsdottir, Anna

AU - Sveinsson, Olafur A.

AU - Sigurdardottir, Gudrun R.

AU - Sævarsdóttir, Sædís

AU - Ivarsdottir, Erna V.

AU - Stefánsdóttir, Lilja

AU - Gunnarsson, Bjarni

AU - Muhlestein, Joseph B.

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AU - Jones, David A.

AU - Nadauld, Lincoln D.

AU - Hartmann, Annette M.

AU - Rujescu, Dan

AU - Strupp, Michael

AU - Walters, Guðmundur Bragi

AU - Thorgeirsson, Thorgeir E.

AU - Jónsdóttir, Ingileif

AU - Holm, Hilma

AU - Thorleifsson, Gudmar

AU - Gudbjartsson, Daniel F.

AU - Sulem, Patrick

AU - Stefansson, Hreinn

AU - Stefansson, Kari

N1 - Funding Information: We thank the participants in this study for their valuable contribution to research. We also thank our colleagues at deCODE who contributed to genotyping and analysis of the WGS data. This research was conducted using the UK Biobank Resource (application number 24898). We acknowledge Stacey Knight, Tyler Barker, Jeffrey L. Anderson, and John F. Carlquist for their contribution to the HerediGene: Population study. We acknowledge the participants and investigators of the FinnGen study. The financial support from the European Commission to the NeuroPain project (FP7#HEALTH-2013-602891-2) and painFACT project (H2020-2020-848099), and the National Institutes of Health (R01DE022905) is acknowledged. Publisher Copyright: © 2021, The Author(s).

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Y1 - 2021/10/7

N2 - Vertigo is the leading symptom of vestibular disorders and a major risk factor for falls. In a genome-wide association study of vertigo (Ncases = 48,072, Ncontrols = 894,541), we uncovered an association with six common sequence variants in individuals of European ancestry, including missense variants in ZNF91, OTOG, OTOGL, and TECTA, and a cis-eQTL for ARMC9. The association of variants in ZNF91, OTOGL, and OTOP1 was driven by an association with benign paroxysmal positional vertigo. Using previous reports of sequence variants associating with age-related hearing impairment and motion sickness, we found eight additional variants that associate with vertigo. Although disorders of the auditory and the vestibular system may co-occur, none of the six genome-wide significant vertigo variants were associated with hearing loss and only one was associated with age-related hearing impairment. Our results uncovered sequence variants associating with vertigo in a genome-wide association study and implicated genes with known roles in inner ear development, maintenance, and disease.

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KW - Genome-Wide Association Study

KW - Humans

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KW - Mutation, Missense

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A genome-wide meta-analysis uncovers six sequence variants conferring risk of vertigo

Abstract

Bibliographical note

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