Age-related hearing impairment (ARHI) is the most common sensory impairment in the aging population; a third of individuals are affected by disabling hearing loss by the age of 65. It causes social isolation and depression and has recently been identified as a risk factor for dementia. The genetic risk factors and underlying pathology of ARHI are largely unknown, meaning that targets for new therapies remain elusive, yet heritability estimates range between 35% and 55%. We performed genome-wide association studies (GWASs) for two self-reported hearing phenotypes, using more than 250,000 UK Biobank (UKBB) volunteers aged between 40 and 69 years. Forty-four independent genome-wide significant loci (p < 5E-08) were identified, considerably increasing the number of established trait loci. Thirty-four loci are novel associations with hearing loss of any form, and only one of the ten known hearing loci has a previously reported association with an ARHI-related trait. Gene sets from these loci are enriched in auditory processes such as synaptic activities, nervous system processes, inner ear morphology, and cognition, while genetic correlation analysis revealed strong positive correlations with multiple personality and psychological traits for the first time. Immunohistochemistry for protein localization in adult mouse cochlea implicate metabolic, sensory, and neuronal functions for NID2, CLRN2, and ARHGEF28. These results provide insight into the genetic landscape underlying ARHI, opening up novel therapeutic targets for further investigation. In a wider context, our study also highlights the viability of using self-report phenotypes for genetic discovery in very large samples when deep phenotyping is unavailable.
Understanding genetic and environmental causes of age-related hearing loss and tinnitus
The aims of this research are:
i) Understand the genetic and environmental causes of age-related hearing loss (ARHL) and tinnitus
ii) Understand interactions between genetic and environmental causes
iii) Identify common genetic or environmental factors associated with ARHL, vision loss and cognitive decline.
ARHL is strongly heritable, but there is limited understanding of the genes associated with ARHL. Declines in hearing, vision and cognition are correlated, suggesting that they share common causal pathways. Recent research suggests that environmental factors (noise, smoking, alcohol consumption) moderate ARHL. Some lifestyle-related factors may interact with genetic factors to increase susceptibility to ARHL. This research will improve prevention and treatment of age-related hearing loss (ARHL). In the UK in 2011, 10 million people had hearing loss. Hearing loss does not just impact on communication; it is also associated with loneliness and depression, cognitive decline and reduced physical well-being. With an ageing society, the number of people with hearing loss is increasing, and hearing loss will be in the top 10 disease burdens by 2030. An international report ?Evaluation of the Social and Economic Costs of Hearing Impairment? calculated that hearing loss costs Europe ?213 billion per year. We will discover genes involved with ARHL, and identify any overlap with vision and cognition. We will test the idea that genetic factors interact with environmental and lifestyle factors to make people more susceptible to hearing loss. This is done by comparing genetic markers across participants with hearing and lifestyle measures. Data are available in cross section (collected at 1 point in time) as well as longitudinally (3-5 years later). We will be able to test whether factors that are associated with poor hearing in cross section are also associated with decline in hearing over time.
Participants for whom hearing, tinnitus and genome-wide association data are available (Digit triplet test, N=164,770; Self-report hearing, N=502,642; tinnitus, N=171,736)
|Lead investigator:||Dr Piers Dawes|
|Lead institution:||University of Manchester|
1 related Return
|Return ID||App ID||Description||Archive Date|
|3871||11516||GWAS Identifies 44 Independent Associated Genomic Loci for Self-Reported Adult Hearing Difficulty in UK Biobank||28 Sep 2021|
|3084||GWAS Identifies 44 Independent Associated Genomic Loci for Self-Reported Adult Hearing Difficulty in UK Biobank||Wells et al||2019||AJHG (2019)|