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

Ívarsdóttir, Erna V.; Hólm, Hilma; Benónísdóttir, Stefania; Ólafsdóttir, Þórhildur; Sveinbjörnsson, Garðar; Þorleifsson, Guðmar; Halldorsson, Gisli H.; Hjorleifsson, Kristjan E; Melsted, Páll; Gylfason, Arnaldur; Arnadottir, Gudny A.; Oddsson, Ásmundur; Jensson, Brynjar O.; Jónasdóttir, Áslaug; Jónasdóttir, Aðalbjörg; Juliusdottir, Thorhildur; Stefánsdóttir, Lilja; Tragante, Vinicius; Halldórsson, Bjarni V.; Petersen, Hannes; Þorgeirsson, Guðmundur; Þorsteinsdóttir, Unnur; Sulem, Patrick; Hinriksdottir, Ingibjörg; Jónsdóttir, Ingileif; Guðbjartsson, Daníel F.; Stefánsson, Kāri

doi:10.1038/s42003-021-02224-9

Cited by 39 publications

(47 citation statements)

References 72 publications

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“…Only a minority of variants included in burden tests have been classified as pathogenic by ClinVar (Supplementary Data 9 ) suggesting that our analysis has detected additional, risk-associated variants with variable penetrance in Mendelian hearing loss genes. We also identified single-variant associations in two genes that cause autosomal dominant hearing loss: TBC1D24 Asn307Ser, also recently reported by Ivarsdottir et al 18 , was implicated as pathogenic in two unrelated families 39 , and COL11A2 Phe80Ser, which has not yet been classified as pathogenic but is predicted deleterious, lies in a domain (Laminin G-like/NC4) that harbors other mutations causing non-syndromic hearing loss 40 .…”

Section: Resultssupporting

confidence: 76%

“…TMPRSS3 is a type II membrane serine protease that localizes to the endoplasmic reticulum and plasma membranes, and is expressed in hair cells and supporting cells in the organ of Corti, the spiral ganglion, and the stria vascularis in the ear 29 – 31 . Mutations in TMPRSS3 cause congenital and childhood-onset autosomal recessive hearing loss 32 but there is also evidence for hearing deficits in heterozygous carriers 18 .…”

Section: Resultsmentioning

confidence: 99%

“…Genome-wide association studies (GWAS) of hearing loss in adults have identified 61 common variant loci associated with the trait in Europeans 13 – 20 . Three of these studies 18 – 20 have included genotyping and imputed data from UK Biobank as well. While the majority of these studies have established a common variant contribution to adult hearing loss, few reports have addressed the contibution of rare and low-frequency variation 21 .…”

Section: Introductionmentioning

confidence: 99%

“…Recently, Ivarsdottir et al 18 published association results with hearing loss on ~50,000 Icelandic individuals with whole-genome sequence and ~50,000 individuals from UKB with exome sequence data, with imputation of larger samples into these variant sets. We have now expanded the rare variant analysis to exome-sequences from ~294,710 individuals in UKB and ~143,286 individuals from three other datasets.…”

Section: Introductionmentioning

confidence: 99%

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Population-scale analysis of common and rare genetic variation associated with hearing loss in adults

et al. 2022

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To better understand the genetics of hearing loss, we performed a genome-wide association meta-analysis with 125,749 cases and 469,497 controls across five cohorts. We identified 53/c loci affecting hearing loss risk, including common coding variants in COL9A3 and TMPRSS3. Through exome sequencing of 108,415 cases and 329,581 controls, we observed rare coding associations with 11 Mendelian hearing loss genes, including additive effects in known hearing loss genes GJB2 (Gly12fs; odds ratio [OR] = 1.21, P = 4.2 × 10−11) and SLC26A5 (gene burden; OR = 1.96, P = 2.8 × 10−17). We also identified hearing loss associations with rare coding variants in FSCN2 (OR = 1.14, P = 1.9 × 10−15) and KLHDC7B (OR = 2.14, P = 5.2 × 10−30). Our results suggest a shared etiology between Mendelian and common hearing loss in adults. This work illustrates the potential of large-scale exome sequencing to elucidate the genetic architecture of common disorders where both common and rare variation contribute to risk.

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Section: Resultssupporting

confidence: 76%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Population-scale analysis of common and rare genetic variation associated with hearing loss in adults

et al. 2022

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“…In addition, we find that homozygotes of the EBAG9 variant have fewer children and a later age at first child than wildtypes (Supplementary Figure S6). The association of C10orf90 with hearing loss was published during the revision of this manuscript 37 . We thus provide a well-powered replication and additional information on disease onset (Figure 5).…”

Section: Figure 2 Schema Of Different Effect Sizes Of Heterozygous (Mono-allelic) Vs Bi-allelic Variant Statesmentioning

confidence: 99%

Mono- and bi-allelic effects of coding variants on disease in 176,899 Finns

Heyne

Karjalainen

Karczewski

et al. 2021

Preprint

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Identifying Mendelian diseases with recessive inheritance is challenging as the majority of cases are caused by compound heterozygous genotypes which require sequencing data in families to definitively identify. Bottleneck events, such as in the Finnish population, enrich specific homozygous variants to higher frequencies and thus facilitate identification of disease associations through easily recognized homozygous genotypes. Here, we study homozygous and heterozygous effects of 82,516 coding variants on 2,444 disease endpoints using nationwide electronic health record (EHR) data of 176,899 Finns. We find known and novel associations to homozygous genotypes across a broad spectrum of phenotypes such as retinal dystrophy, adult-onset cataract and female infertility (13/20 of which would have been missed by the traditional additive GWAS model). With these results, and supporting simulations, we demonstrate the added benefit of homozygous scans in GWAS. We further use these results to explore inheritance patterns of known Mendelian variants. We find many Mendelian variants whose inheritance cannot be adequately described with the traditional definition of dominant or recessive. In particular, we find disease risk in heterozygous carriers of variants known to cause disease with recessive inheritance, as well as for variants labeled benign in ClinVar. Our results demonstrate how biobank efforts, particularly in founder populations, can broaden our understanding of the impact of genetic variants.

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Comprehensive association analysis of speech recognition thresholds after cisplatin‐based chemotherapy in survivors of adult‐onset cancer

et al. 2022

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Purpose Deficits in speech understanding constitute one of the most severe consequences of hearing loss. Here we investigate the clinical and genetic risk factors for symmetric deterioration of speech recognition thresholds (SRT) among cancer survivors treated with cisplatin. Methods SRT was measured using spondaic words and calculating the mean of measurements for both ears with symmetric SRT values. For clinical associations, SRT‐based hearing disability (SHD) was defined as SRT≥15 dB hearing loss and clinical variables were derived from the study dataset. Genotyped blood samples were used for GWAS with rank‐based inverse normal transformed SRT values as the response variable. Age was used as a covariate in association analyses. Results SHD was inversely associated with self‐reported health ( p = 0.004). Current smoking ( p = 0.002), years of smoking ( p = 0.02), BMI ( p < 0.001), and peripheral motor neuropathy ( p = 0.003) were positively associated with SHD, while physical activity was inversely associated with SHD ( p = 0.005). In contrast, cumulative cisplatin dose, peripheral sensory neuropathy, hypertension, and hypercholesterolemia were not associated with SHD. Although no genetic variants had an association p value < 5 × 10 −8 , 22 genetic variants were suggestively associated ( p < 10 −5 ) with SRT deterioration. Three of the top variants in 10 respective linkage disequilibrium regions were either positioned within the coding sequence or were eQTLs for genes involved in neuronal development ( ATE1 , ENAH, and ZFHX3 ). Conclusion Current results improve our understanding of risk factors for SRT deterioration in cancer survivors. Higher BMI, lower physical activity, and smoking are associated with SHD. Larger samples would allow for expansion of the current findings on the genetic architecture of SRT.

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

Cited by 39 publications

References 72 publications

Population-scale analysis of common and rare genetic variation associated with hearing loss in adults

Population-scale analysis of common and rare genetic variation associated with hearing loss in adults

Mono- and bi-allelic effects of coding variants on disease in 176,899 Finns

Comprehensive association analysis of speech recognition thresholds after cisplatin‐based chemotherapy in survivors of adult‐onset cancer

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