Familial Aggregation of Pure Tone Hearing Thresholds in an Aging European Population

Hendrickx, Jan; Huyghe, Jeroen R.; Topsakal, Vedat; Demeester, Kelly; Wienker, Thomas F.; Laer, Lut Van; Eyken, Els Van; Fransén, Erik; Mäki‐Torkko, Elina; Hannula, Samuli; Parving, Agnete; Jensen, Martin; Tropitzsch, Anke; Bonaconsa, Amanda; Mazzoli, Manuela; Espeso, Angeles; Verbruggen, Katia; Huyghe, Joke; Huygen, P.L.M.; Kremer, Hannie; Kunst, Sylvia J. W.; Díaz-Lacava, Amalia; Steffens, Michael; Pyykkö, Ilmari; Dhooge, Ingeborg; Stephens, Dafydd; Orzan, Eva; Pfister, Markus; Bille, Mikkel; Sorri, Martti; Cremers, C.W.R.J.; Camp, Guy Van; Heyning, Paul Van de

doi:10.1097/mao.0b013e318288646a

Cited by 17 publications

(12 citation statements)

References 29 publications

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“…ARHL is a multifactorial disease governed by both genetic and environmental factors (noise, ototoxic drugs), and modulated by the interaction between them (Bowl & Dawson, 2019). Heritability estimates for ARHL lie between 35% and 70% (Christensen, Frederiksen, Frederiksen, & Hoffman, 2001;Gates, Couropmitree, Couropmitree, & Myers, 1999;Hendrickx et al, 2013;Raynor et al, 2009) and noise exposure is a major environmental component that is difficult to separate from the underlying genetic basis (Liberman, 2017;Van Eyken, Van Camp, & Van Laer, 2007). Studies in aged animals and human temporal bones have given great insight into the histological deficit with degenerative changes in the sensory hair cells, the spiral ganglion neurons, and the stria vascularis predominantly described; Figure 1 (Keithley, 2019;Ohlemiller, 2004;Schuknecht, 1964;Schuknecht & Gacek, 1993).…”

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confidence: 99%

Age‐related hearing loss: Why we need to think about sex as a biological variable

Nolan

2020

J of Neuroscience Research

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It has long been known that age‐related hearing loss (ARHL) is more common, more severe, and with an earlier onset in men compared to women. Even in the absence of confounding factors such as noise exposure, these sexdifferences in susceptibility to ARHL remain. In the last decade, insight into the pleiotrophic nature by which estrogen signaling can impact multiple signaling mechanisms to mediate downstream changes in gene expression and/or elicit rapid changes in cellular function has rapidly gathered pace, and a role for estrogen signaling in the biological pathways that confer neuroprotection is becoming undeniable. Here I review the evidence why we need to consider sex as a biological variable (SABV) when investigating the etiology of ARHL. Loss of auditory function with aging is frequency‐specific and modulated by SABV. Evidence also suggests that differences in cochlear physiology between women and men are already present from birth. Understanding the molecular basis of these sex differences in ARHL will accelerate the development of precision medicine therapies for ARHL.

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confidence: 99%

Age‐related hearing loss: Why we need to think about sex as a biological variable

Nolan

2020

J of Neuroscience Research

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“…Environmental factors are thought to account for about half the phenotypic variance of presbycusis (10). Heritability indices of 0.35 to 0.70 have been reported in studies based on hearing thresholds in twins (14), families (15,16), or individuals with self-reported hearing impairment (17).…”

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confidence: 99%

Ultrarare heterozygous pathogenic variants of genes causing dominant forms of early-onset deafness underlie severe presbycusis

Boucher

Tai

Delmaghani

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Presbycusis, or age-related hearing loss (ARHL), is a major public health issue. About half the phenotypic variance has been attributed to genetic factors. Here, we assessed the contribution to presbycusis of ultrarare pathogenic variants, considered indicative of Mendelian forms. We focused on severe presbycusis without environmental or comorbidity risk factors and studied multiplex family age-related hearing loss (mARHL) and simplex/sporadic age-related hearing loss (sARHL) cases and controls with normal hearing by whole-exome sequencing. Ultrarare variants (allele frequency [AF] < 0.0001) of 35 genes responsible for autosomal dominant early-onset forms of deafness, predicted to be pathogenic, were detected in 25.7% of mARHL and 22.7% of sARHL cases vs. 7.5% of controls (P = 0.001); half were previously unknown (AF < 0.000002). MYO6, MYO7A, PTPRQ, and TECTA variants were present in 8.9% of ARHL cases but less than 1% of controls. Evidence for a causal role of variants in presbycusis was provided by pathogenicity prediction programs, documented haploinsufficiency, three-dimensional structure/function analyses, cell biology experiments, and reported early effects. We also established Tmc1N321I/+ mice, carrying the TMC1:p.(Asn327Ile) variant detected in an mARHL case, as a mouse model for a monogenic form of presbycusis. Deafness gene variants can thus result in a continuum of auditory phenotypes. Our findings demonstrate that the genetics of presbycusis is shaped by not only well-studied polygenic risk factors of small effect size revealed by common variants but also, ultrarare variants likely resulting in monogenic forms, thereby paving the way for treatment with emerging inner ear gene therapy.

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“…Heritability estimates for age-related hearing loss range as high as 36 and 70% [7][8][9][10][11] suggesting that genetics, along with environmental factors, play a significant role in determining an individual's risk for developing hearing loss. Genome-wide association studies (GWAS) of hearing loss in adults have identified 58 loci associated with the trait in Europeans [12][13][14][15][16] .…”

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confidence: 99%

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

Praveen

Dobbyn

Gurski

et al. 2021

Preprint

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Understanding the genetic underpinnings of disabling hearing loss, which affects ~466 million people worldwide, can provide avenues for new therapeutic target development. We performed a genome-wide association meta-analysis of hearing loss with 125,749 cases and 469,497 controls across five cohorts, including UK Biobank, Geisinger DiscovEHR, the Malmö Diet and Cancer Study, the Mount Sinai BioMe Personalized Medicine Cohort, and FinnGen. We identified 53 loci affecting hearing loss risk, 18 of which are novel, including coding variants in COL9A3 and TMPRSS3. Through exome-sequencing of 108,415 cases and 329,581 controls from the same cohorts, we identified an association with rare predicted loss-of-function variants in a gene that has been uncharacterized in hearing loss, KLHDC7B (odds ratio [OR] = 2.14, P = 5.2 × 10-30), and with coding variants in two genes previously implicated in animal models of hearing loss (SYNJ2, OR = 1.31, P = 1.3 × 10-14; FSCN2, OR = 1.24, P = 4.1 × 10-15). We also observed single-variant and gene-burden associations with 11 genes known to cause Mendelian forms of hearing loss, including an increased risk in heterozygous carriers of mutations in the autosomal recessive hearing loss genes GJB2 (Gly12fs; OR = 1.21, P = 4.2 × 10-11) and SLC26A5 (gene burden; OR = 1.96, P = 2.8 × 10-17). Our results show that Mendelian hearing loss genes contribute to the burden of hearing loss in the adult population, and suggest a shared etiology between common and rare forms of hearing loss. This work illustrates the potential of large-scale exome sequencing to elucidate the genetic architecture of common traits in which risk is modulated by both common and rare variation.

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Familial Aggregation of Pure Tone Hearing Thresholds in an Aging European Population

Abstract: Our results indicate that there is a substantial shared familial effect in ARHI. We found that familial aggregation of ARHI is markedly higher in the low frequencies and that there is a trend toward higher familial aggregation in female compared with male subjects.

Cited by 17 publications

References 29 publications

Age‐related hearing loss: Why we need to think about sex as a biological variable

Age‐related hearing loss: Why we need to think about sex as a biological variable

Ultrarare heterozygous pathogenic variants of genes causing dominant forms of early-onset deafness underlie severe presbycusis

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

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