A combined genome-wide association and molecular study of age-related hearing loss in H. sapiens

Abstract

Background Sensorineural hearing loss is one of the most common sensory deficiencies. However, the molecular contribution to age-related hearing loss is not fully elucidated. Methods We performed genome-wide association studies (GWAS) for hearing loss-related traits in the UK Biobank (N = 362,396) and selected a high confidence set of ten hearing-associated gene products for staining in human cochlear samples: EYA4, LMX1A, PTK2/FAK, UBE3B, MMP2, SYNJ2, GRM5, TRIOBP, LMO-7, and NOX4. Results All proteins were found to be expressed in human cochlear structures. Our findings illustrate cochlear structures that mediate mechano-electric transduction of auditory stimuli, neuronal conductance, and neuronal plasticity to be involved in age-related hearing loss. Conclusions Our results suggest common genetic variation to influence structural resilience to damage as well as cochlear recovery after trauma, which protect against accumulated damage to cochlear structures and the development of hearing loss over time.

Genome-wide association meta-analysis identifies 48 risk variants and highlights the role of the stria vascularis in hearing loss

“…62 Indeed, these findings are consistent with a recent GWAS performed on the UKBB that localized a number of lead SNPs in cells from the post-natal mouse cochleae using scRNA-seq data 12 or in the human cochlea (mainly in type I SGN, or hair cells) using immunohistochemistry on samples collected from individuals with life-threatening posterior cranial fossa meningioma compressing the brain stem. 63 These included EYA4, LMX1A, PTK2/ FAK, UBE3B, MMP2, SYNJ2, GRM5, TRIOBP, LMO-7, and NOX4. Consistent with their findings, we also identified SPTBN1, a mouse ortholog Spectrin expressed in the cuticular plate at the base of the stereocilia, deletion of which causes profound deafness.…”

Age-Related Hearing Loss: Sensory and Neural Etiology and Their Interdependence

“…In humans, a loss of OHCs is followed by IHCs that progresses around 65 years of age (Nadol Jr and Xu, 1992 ; Rauch et al, 2001 ; Liu et al, 2021 ). A most detailed description was recently provided that shows a comparable loss of OHCs and IHCs (Wu et al, 2021 ) that reduces IHCs ~50% in the base of ~75-year-old humans, compared to ~40% in the same region of OHCs ( Figures 1C,D ).…”

“…To date, no one has succeeded in producing both types of the organ of Corti sensory hair cells in vitro in the correct proportion and disparity distribution needed for the restoration of hair cells within the organ of Corti. Many issues remain open, but we have no solution at hand, turning the feasibility of producing hair cells with following repopulation of the damaged organ of Corti into a future option (Liu et al, 2021 ). Restoration of the flat auditory non-sensory epithelium between the lingering patches of hair cells (Pirvola et al, 2002 ; Kiernan et al, 2005 ; Soukup et al, 2009 ; Pan et al, 2012 ; Duncan and Fritzsch, 2013 ; Herranen et al, 2020 ) also requires restoration of innervation to the newly molded hair cells.…”

“…In summary, the progressive loss of cochlear hair cells depends on a large number of genes (Liu et al, 2021 ) that results in the flat auditory epithelium and requires a re-establishment of normal hair cells for hearing restoration. Alternative approaches, such as incorporating induced hair cells into the cochlea, are challenging.…”

Longitudinal fundus imaging and its genome-wide association analysis provide evidence for a human retinal aging clock

“…26 MEF2C has reported roles in numerous age-related conditions, including Alzheimer's disease 27 and muscle wasting in cancer 28 and GRM is associated with age-related hearing loss. 29 Additional candidates are reported to be involved in cancer prognosis and progression, including TSPAN11, 30 NKX6-1, 31 and SLC16A1. 32 Gene enrichment analysis 33 identified significant associations (adjusted p < 0.05) between our gene candidates and macular thickness and degeneration, as seen in previous human GWAS studies 34 and cataract formation (Elsevier pathway collection), 35 as well as non-eye related diseases such as bone mineralization, tumor suppression, and Amyloid Precursor Protein pathways (Biocarta).…”