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

Erna V. Ívarsdóttir; Hilma Hólm; Stefanía Benónísdóttir; Þórhildur Ólafsdóttir; Garðar Sveinbjörnsson; Gudmar Thorleifsson; Hannes P. Eggertsson; Gisli H. Halldorsson; Kristjan E. Hjörleifsson; Pall Melsted; Arnaldur Gylfason; Gudny A. Arnadottir; Ásmundur Oddsson; Brynjar O. Jensson; Áslaug Jónasdóttir; Adalbjorg Jonasdottir; Thorhildur Juliusdottir; Lilja Stefánsdóttir; Vinicius Tragante; Bjarni V. Halldorsson; Hannes Petersen; Gudmundur Thorgeirsson; Unnur Þorsteinsdóttir; Patrick Sulem; Ingibjörg Hinriksdóttir; Ingileif Jónsdottir; Daniel F. Guðbjartsson; Kari Stefánsson

doi:10.1038/s42003-021-02224-9

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

Erna V. Ívarsdóttir
, Hilma Hólm
, Stefanía Benónísdóttir
, Þórhildur Ólafsdóttir
, Garðar Sveinbjörnsson
, Gudmar Thorleifsson
, Hannes P. Eggertsson
, Gisli H. Halldorsson
, Kristjan E. Hjörleifsson
, Pall Melsted
, Arnaldur Gylfason
, Gudny A. Arnadottir
, Ásmundur Oddsson
, Brynjar O. Jensson
, Áslaug Jónasdóttir
, Adalbjorg Jonasdottir
, Thorhildur Juliusdottir
, Lilja Stefánsdóttir
, Vinicius Tragante
, Bjarni V. Halldorsson

Hannes Petersen, Gudmundur Thorgeirsson, Unnur Þorsteinsdóttir, Patrick Sulem, Ingibjörg Hinriksdóttir, Ingileif Jónsdottir, Daniel F. Guðbjartsson, Kari Stefánsson

Reykjavik University, University of Iceland

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	706
Pages (from-to)	706
Journal	Communications Biology
Volume	4
Issue number	1
DOIs	https://doi.org/10.1038/s42003-021-02224-9
Publication status	Published - 9 Jun 2021

Bibliographical note

Other keywords

Adult
Aged
Aged, 80 and over
Aging/genetics
Female
Genes/genetics
Genetic Predisposition to Disease
Genetic Variation/genetics
Genome-Wide Association Study
Hearing Loss/genetics
Humans
Male
Middle Aged
Risk Factors

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10.1038/s42003-021-02224-9

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Ívarsdóttir, E. V., Hólm, H., Benónísdóttir, S., Ólafsdóttir, Þ., Sveinbjörnsson, G., Thorleifsson, G., Eggertsson, H. P., Halldorsson, G. H., Hjörleifsson, K. E., Melsted, P., Gylfason, A., Arnadottir, G. A., Oddsson, Á., Jensson, B. O., Jónasdóttir, Á., Jonasdottir, A., Juliusdottir, T., Stefánsdóttir, L., Tragante, V., ... Stefánsson, K. (2021). The genetic architecture of age-related hearing impairment revealed by genome-wide association analysis. Communications Biology, 4(1), 706. Article 706. https://doi.org/10.1038/s42003-021-02224-9

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title = "The genetic architecture of age-related hearing impairment revealed by genome-wide association analysis",

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.",

keywords = "Adult, Aged, Aged, 80 and over, Aging/genetics, Female, Genes/genetics, Genetic Predisposition to Disease, Genetic Variation/genetics, Genome-Wide Association Study, Hearing Loss/genetics, Humans, Male, Middle Aged, Risk Factors",

author = "{\'I}varsd{\'o}ttir, \{Erna V.\} and Hilma H{\'o}lm and Stefan{\'i}a Ben{\'o}n{\'i}sd{\'o}ttir and {\TH}{\'o}rhildur {\'O}lafsd{\'o}ttir and Gar{\dh}ar Sveinbj{\"o}rnsson and Gudmar Thorleifsson and Eggertsson, \{Hannes P.\} and Halldorsson, \{Gisli H.\} and Hj{\"o}rleifsson, \{Kristjan E.\} and Pall Melsted and Arnaldur Gylfason and Arnadottir, \{Gudny A.\} and {\'A}smundur Oddsson and Jensson, \{Brynjar O.\} and {\'A}slaug J{\'o}nasd{\'o}ttir and Adalbjorg Jonasdottir and Thorhildur Juliusdottir and Lilja Stef{\'a}nsd{\'o}ttir and Vinicius Tragante and Halldorsson, \{Bjarni V.\} and Hannes Petersen and Gudmundur Thorgeirsson and Unnur {\TH}orsteinsd{\'o}ttir and Patrick Sulem and Ingibj{\"o}rg Hinriksd{\'o}ttir and Ingileif J{\'o}nsdottir and Gu{\dh}bjartsson, \{Daniel F.\} and Kari Stef{\'a}nsson",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = jun,

day = "9",

doi = "10.1038/s42003-021-02224-9",

language = "English",

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Ívarsdóttir, EV, Hólm, H, Benónísdóttir, S, Ólafsdóttir, Þ, Sveinbjörnsson, G, Thorleifsson, G, Eggertsson, HP, Halldorsson, GH, Hjörleifsson, KE, Melsted, P, Gylfason, A, Arnadottir, GA, Oddsson, Á, Jensson, BO, Jónasdóttir, Á, Jonasdottir, A, Juliusdottir, T, Stefánsdóttir, L, Tragante, V, Halldorsson, BV, Petersen, H , Thorgeirsson, G , Þorsteinsdóttir, U, Sulem, P, Hinriksdóttir, I, Jónsdottir, I, Guðbjartsson, DF & Stefánsson, K 2021, 'The genetic architecture of age-related hearing impairment revealed by genome-wide association analysis', Communications Biology, vol. 4, no. 1, 706, pp. 706. https://doi.org/10.1038/s42003-021-02224-9

TY - JOUR

T1 - The genetic architecture of age-related hearing impairment revealed by genome-wide association analysis

AU - Ívarsdóttir, Erna V.

AU - Hólm, Hilma

AU - Benónísdóttir, Stefanía

AU - Ólafsdóttir, Þórhildur

AU - Sveinbjörnsson, Garðar

AU - Thorleifsson, Gudmar

AU - Eggertsson, Hannes P.

AU - Halldorsson, Gisli H.

AU - Hjörleifsson, Kristjan E.

AU - Melsted, Pall

AU - Gylfason, Arnaldur

AU - Arnadottir, Gudny A.

AU - Oddsson, Ásmundur

AU - Jensson, Brynjar O.

AU - Jónasdóttir, Áslaug

AU - Jonasdottir, Adalbjorg

AU - Juliusdottir, Thorhildur

AU - Stefánsdóttir, Lilja

AU - Tragante, Vinicius

AU - Halldorsson, Bjarni V.

AU - Petersen, Hannes

AU - Thorgeirsson, Gudmundur

AU - Þorsteinsdóttir, Unnur

AU - Sulem, Patrick

AU - Hinriksdóttir, Ingibjörg

AU - Jónsdottir, Ingileif

AU - Guðbjartsson, Daniel F.

AU - Stefánsson, Kari

PY - 2021/6/9

Y1 - 2021/6/9

N2 - 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.

AB - 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.

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Aging/genetics

KW - Female

KW - Genes/genetics

KW - Genetic Predisposition to Disease

KW - Genetic Variation/genetics

KW - Genome-Wide Association Study

KW - Hearing Loss/genetics

KW - Humans

KW - Male

KW - Middle Aged

KW - Risk Factors

UR - https://www.scopus.com/pages/publications/85107417912

U2 - 10.1038/s42003-021-02224-9

DO - 10.1038/s42003-021-02224-9

M3 - Article

C2 - 34108613

SN - 2399-3642

VL - 4

SP - 706

JO - Communications Biology

JF - Communications Biology

IS - 1

M1 - 706

ER -

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

Abstract

Bibliographical note

Other keywords

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