The Genetic Architecture of Age-related Hearing Impairment Revealed by Genome-wide Association Analysis

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 and OR = 4.2 for heterozygotes, P = 5.7 × 10, 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.

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References

Gudbjartsson D, Helgason H, Gudjonsson S, Zink F, Oddson A, Gylfason A . Large-scale whole-genome sequencing of the Icelandic population. Nat Genet. 2015; 47(5):435-44. DOI: 10.1038/ng.3247. View

Wesdorp M, van de Kamp J, Hensen E, Schraders M, Oostrik J, Yntema H . Broadening the phenotype of DFNB28: Mutations in TRIOBP are associated with moderate, stable hereditary hearing impairment. Hear Res. 2017; 347:56-62. DOI: 10.1016/j.heares.2016.12.017. View

Eggertsson H, Kristmundsdottir S, Beyter D, Jonsson H, Skuladottir A, Hardarson M . GraphTyper2 enables population-scale genotyping of structural variation using pangenome graphs. Nat Commun. 2019; 10(1):5402. PMC: 6881350. DOI: 10.1038/s41467-019-13341-9. View

Santos R, Hassan M, Sikandar S, Lee K, Ali G, Martin Jr P . DFNB68, a novel autosomal recessive non-syndromic hearing impairment locus at chromosomal region 19p13.2. Hum Genet. 2006; 120(1):85-92. PMC: 2909094. DOI: 10.1007/s00439-006-0188-z. View

Kent W, Sugnet C, Furey T, Roskin K, Pringle T, Zahler A . The human genome browser at UCSC. Genome Res. 2002; 12(6):996-1006. PMC: 186604. DOI: 10.1101/gr.229102. View

Venkatesh M, Moorchung N, Puri B . Genetics of non syndromic hearing loss. Med J Armed Forces India. 2015; 71(4):363-8. PMC: 4646903. DOI: 10.1016/j.mjafi.2015.07.003. View

Lucotte G, Dieterlen F . The 35delG mutation in the connexin 26 gene (GJB2) associated with congenital deafness: European carrier frequencies and evidence for its origin in ancient Greece. Genet Test. 2005; 9(1):20-5. DOI: 10.1089/gte.2005.9.20. View

OLeary N, Wright M, Brister J, Ciufo S, Haddad D, McVeigh R . Reference sequence (RefSeq) database at NCBI: current status, taxonomic expansion, and functional annotation. Nucleic Acids Res. 2015; 44(D1):D733-45. PMC: 4702849. DOI: 10.1093/nar/gkv1189. View

Jonsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E . Whole genome characterization of sequence diversity of 15,220 Icelanders. Sci Data. 2017; 4:170115. PMC: 5607473. DOI: 10.1038/sdata.2017.115. View

10.

Welch D, Dawes P . Childhood hearing is associated with growth rates in infancy and adolescence. Pediatr Res. 2007; 62(4):495-8. DOI: 10.1203/PDR.0b013e3181425869. View

11.

Wain L, Shrine N, Miller S, Jackson V, Ntalla I, Artigas M . Novel insights into the genetics of smoking behaviour, lung function, and chronic obstructive pulmonary disease (UK BiLEVE): a genetic association study in UK Biobank. Lancet Respir Med. 2015; 3(10):769-81. PMC: 4593935. DOI: 10.1016/S2213-2600(15)00283-0. View

12.

COLES R . Epidemiology of tinnitus: (1) prevalence. J Laryngol Otol Suppl. 1984; 9:7-15. DOI: 10.1017/s1755146300090041. View

13.

Hietanen A, Era P, Henrichsen J, Rosenhall U, Sorri M, Heikkinen E . Hearing among 75-year-old people in three Nordic localities: a comparative study. Int J Audiol. 2005; 44(9):500-8. DOI: 10.1080/14992020500189112. View

14.

Battelino S, Klancar G, Kovac J, Battelino T, Trebusak Podkrajsek K . TMPRSS3 mutations in autosomal recessive nonsyndromic hearing loss. Eur Arch Otorhinolaryngol. 2015; 273(5):1151-4. DOI: 10.1007/s00405-015-3671-0. View

15.

Higgins J, Thompson S . Quantifying heterogeneity in a meta-analysis. Stat Med. 2002; 21(11):1539-58. DOI: 10.1002/sim.1186. View

16.

Atik A . Pathophysiology and treatment of tinnitus: an elusive disease. Indian J Otolaryngol Head Neck Surg. 2014; 66(Suppl 1):1-5. PMC: 3918281. DOI: 10.1007/s12070-011-0374-8. View

17.

Grillet N, Schwander M, Hildebrand M, Sczaniecka A, Kolatkar A, Velasco J . Mutations in LOXHD1, an evolutionarily conserved stereociliary protein, disrupt hair cell function in mice and cause progressive hearing loss in humans. Am J Hum Genet. 2009; 85(3):328-37. PMC: 2771534. DOI: 10.1016/j.ajhg.2009.07.017. View

18.

Shen J, Scheffer D, Kwan K, Corey D . SHIELD: an integrative gene expression database for inner ear research. Database (Oxford). 2015; 2015:bav071. PMC: 4513695. DOI: 10.1093/database/bav071. View

19.

McCarthy S, Das S, Kretzschmar W, Delaneau O, Wood A, Teumer A . A reference panel of 64,976 haplotypes for genotype imputation. Nat Genet. 2016; 48(10):1279-83. PMC: 5388176. DOI: 10.1038/ng.3643. View

20.

Morton N . Genetic epidemiology of hearing impairment. Ann N Y Acad Sci. 1991; 630:16-31. DOI: 10.1111/j.1749-6632.1991.tb19572.x. View