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

Creators: Ivarsdottir, Erna V.; Holm, Hilma; Benonisdottir, Stefania; Olafsdottir, Thorhildur; Sveinbjornsson, Gardar; Thorleifsson, Gudmar; Eggertsson, Hannes P.; Halldorsson, Gisli H.; Hjorleifsson, Kristjan E.; Melsted, Páll; Gylfason, Arnaldur; Arnadottir, Gudny A.; Oddsson, Asmundur; Jensson, Brynjar O.; Jonasdottir, Aslaug; Jonasdottir, Adalbjorg; Juliusdottir, Thorhildur; Stefansdottir, Lilja; Tragante, Vinicius; Halldorsson, Bjarni V.; Petersen, Hannes; Thorgeirsson, Gudmundur; Thorsteinsdottir, Unnur; Sulem, Patrick; Hinriksdottir, Ingibjorg; Jonsdottir, Ingileif; Gudbjartsson, Daniel F.; Stefansson, Kari

Abstract

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.

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 http://creativecommons.org/licenses/by/4.0/. 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 http://www.decode.com/summarydata. Code availability: We used the following publicly available software for the whole-genome sequencing process: BWA 0.7.10 mem (https://github.com/lh3/bwa), Picard tools 1.117 (https://broadinstitute.github.io/picard/), SAMtools 1.3 (http://samtools.github.io/), Bedtools v2.25.0-76-g5e7c696z (https://github.com/arq5x/bedtools2/), GraphTyper 1.3 (https://github.com/DecodeGenetics/graphtyper), Variant Effect Predictor (https://github.com/Ensembl/ensembl-vep). 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.

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