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The genetic architecture of age-related hearing impairment revealed by genome-wide association analysis

Ivarsdottir, Erna V. and Holm, Hilma and Benonisdottir, Stefania and Olafsdottir, Thorhildur and Sveinbjornsson, Gardar and Thorleifsson, Gudmar and Eggertsson, Hannes P. and Halldorsson, Gisli H. and Hjorleifsson, Kristjan E. and Melsted, Páll and Gylfason, Arnaldur and Arnadottir, Gudny A. and Oddsson, Asmundur and Jensson, Brynjar O. and Jonasdottir, Aslaug and Jonasdottir, Adalbjorg and Juliusdottir, Thorhildur and Stefansdottir, Lilja and Tragante, Vinicius and Halldorsson, Bjarni V. and Petersen, Hannes and Thorgeirsson, Gudmundur and Thorsteinsdottir, Unnur and Sulem, Patrick and Hinriksdottir, Ingibjorg and Jonsdottir, Ingileif and Gudbjartsson, Daniel F. and Stefansson, Kari (2021) The genetic architecture of age-related hearing impairment revealed by genome-wide association analysis. Communications Biology, 4 . Art. No. 706. ISSN 2399-3642. PMCID PMC8190123. doi:10.1038/s42003-021-02224-9.

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Age-related hearing impairment (ARHI) is the most common sensory disorder in older adults. We conducted a genome-wide association meta-analysis of 121,934 ARHI cases and 591,699 controls from Iceland and the UK. We identified 21 novel sequence variants, of which 13 are rare, under either additive or recessive models. Of special interest are a missense variant in LOXHD1 (MAF = 1.96%) and a tandem duplication in FBF1 covering 4 exons (MAF = 0.22%) associating with ARHI (OR = 3.7 for homozygotes, P = 1.7 × 10⁻²² and OR = 4.2 for heterozygotes, P = 5.7 × 10⁻²⁷, respectively). We constructed an ARHI genetic risk score (GRS) using common variants and showed that a common variant GRS can identify individuals at risk comparable to carriers of rare high penetrance variants. Furthermore, we found that ARHI and tinnitus share genetic causes. This study sheds a new light on the genetic architecture of ARHI, through several rare variants in both Mendelian deafness genes and genes not previously linked to hearing.

Item Type:Article
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URLURL TypeDescription CentralArticle ItemGWAS summary statistics ItemBWA 0.7.10 mem ItemPicard tools 1.117 ItemSAMtools 1.3 ItemBedtools v2.25.0-76-g5e7c696z ItemGraphTyper 1.3 ItemVariant Effect Predictor
Ivarsdottir, Erna V.0000-0002-2069-0681
Holm, Hilma0000-0002-9517-6636
Sveinbjornsson, Gardar0000-0003-2429-9468
Eggertsson, Hannes P.0000-0002-1674-9978
Halldorsson, Gisli H.0000-0001-7067-9862
Hjorleifsson, Kristjan E.0000-0002-7851-1818
Melsted, Páll0000-0002-8418-6724
Arnadottir, Gudny A.0000-0001-6571-423X
Oddsson, Asmundur0000-0002-4606-5163
Tragante, Vinicius0000-0002-8223-8957
Halldorsson, Bjarni V.0000-0003-0756-0767
Thorgeirsson, Gudmundur0000-0003-4623-9087
Thorsteinsdottir, Unnur0000-0002-7049-2827
Sulem, Patrick0000-0001-7123-6123
Jonsdottir, Ingileif0000-0001-8339-150X
Gudbjartsson, Daniel F.0000-0002-5222-9857
Stefansson, Kari0000-0003-1676-864X
Additional Information:© The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit Received 06 August 2020; Accepted 17 May 2021; Published 09 June 2021. We would like to thank all study participants for their valuable contribution to the research. We also thank the staff at NIHSI and deCODE genetics recruitment center and core facilities, and all our colleagues, for their important collaboration on this work. A part of this research has been conducted using the UK Biobank Recourse under application number 56270. Data availability: The authors declare that the data supporting the findings of this study are available within the article, in supplementary files, and upon request. The sequence variants from the Icelandic population whole-genome sequence data have been deposited at the European Variant Archive under accession PRJEB15197. GWAS summary statistics will be made available at Code availability: We used the following publicly available software for the whole-genome sequencing process: BWA 0.7.10 mem (, Picard tools 1.117 (, SAMtools 1.3 (, Bedtools v2.25.0-76-g5e7c696z (, GraphTyper 1.3 (, Variant Effect Predictor ( Author Contributions: E.V.I., H.H., S.B., U.T., P.S., I.H., I.J., D.F.G., and K.S. designed the study and interpreted the results. E.V.I. S.B., G.S., G.Thorleifsson, H.P.E., G.H.H., K.E.H., P.M., A.G., A.O., G.A.A., B.O.J., L.S., B.H., and D.F.G. analyzed the data. As.J. and Ad.J. did the Sanger sequencing. E.V.I., H.H., G.Thorleifsson, T.J., V.T., H.P., G.Thorgeirsson, I.H., and I.J. performed recruitment and phenotyping. The manuscript was drafted by E.V.I., H.H., S.B., T.O., U.T., P.S., I.H., D.F.G., and K.S. All authors contributed to the final version of the manuscript. Competing interests: E.V.I., H.H., S.B., T.O., G.S., G.Thorleifsson, H.P.E., G.H.H., K.E.H., P.M., A.G., G.A.A., A.O., B.O.J., As.J., Ad.J., T.J., L.S., V.T., B.V.H., G.Thorgeirsson., U.T., P.S., I.J., D.F.G., and K.S. are employees of deCODE genetics/Amgen, Inc. H.P. and I.H. have no competing interests to declare. Peer review information: Communications Biology thanks the anonymous reviewers for their contribution to the peer review of this work. Peer Reviewer reports are available.
Funding AgencyGrant Number
UK Biobank Recourse56270
Subject Keywords:Ageing; Genetic association study; Genome-wide association studies
PubMed Central ID:PMC8190123
Record Number:CaltechAUTHORS:20210709-204110916
Persistent URL:
Official Citation:Ivarsdottir, E.V., Holm, H., Benonisdottir, S. et al. The genetic architecture of age-related hearing impairment revealed by genome-wide association analysis. Commun Biol 4, 706 (2021).
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:109760
Deposited By: Tony Diaz
Deposited On:09 Jul 2021 21:12
Last Modified:09 Jul 2021 21:12

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