Biological insights from multi-omic analysis of 31 genomic risk loci for adult hearing difficulty

Abstract

Age-related hearing impairment (ARHI), one of the most common medical conditions, is strongly heritable, yet its genetic causes remain largely unknown. We conducted a metaanalysis of GWAS summary statistics from multiple hearing-related traits in the UK Biobank (n = up to 330,759) and identified 31 genome-wide significant risk loci for self-reported hearing difficulty (p < 5x10-8), of which eight have not been reported previously in the peerreviewed literature. We investigated the regulatory and cell specific expression for these loci by generating mRNA-seq, ATAC-seq, and single-cell RNA-seq from cells in the mouse cochlea. Risk-associated genes were most strongly enriched for expression in cochlear epithelial cells, as well as for genes related to sensory perception and known Mendelian deafness genes, supporting their relevance to auditory function. Regions of the human genome homologous to open chromatin in epithelial cells from the mouse were strongly enriched for heritable risk for hearing difficulty, even after adjusting for baseline effects of evolutionary conservation and cell-type non-specific regulatory regions. Epigenomic and statistical finemapping most strongly supported 50 putative risk genes. Of these, 39 were expressed robustly in mouse cochlea and 16 were enriched specifically in sensory hair cells. These results reveal new risk loci and risk genes for hearing difficulty and suggest an important role for altered gene regulation in the cochlear sensory epithelium.

Genome‐wide association study and polygenic risk score analysis for hearing measures in children

“…In fact, air conduction thresholds are not routinely collected in large-scale population studies. For example, the UK Biobank includes phenotypic information on hearing ability as self-reported hearing difficulty or use of hearing aids (n > 300,000) (Kalra et al, 2020;Wells et al, 2019).…”

Age-Related Changes in the Cochlea and Vestibule: Shared Patterns and Processes

“…Several genome-wide association studies (GWAS) and candidate gene studies have been performed to identify the specific genes contributing to ARHL (reviewed in Ahmadmehrabi et al, 2021). Recent work combining GWAS with other approaches (Nagtegaal et al, 2019;Wells et al, 2019;Kalra et al, 2020), including gene set enrichment analyses, transcriptomic and epigenomic data from the mouse cochlea, as well as immunohistochemistry in the mouse cochlea, implicate a role of at least some of these genes in metabolic, sensory, and neuronal functioning of the cochlea. The genetic contribution to most vestibular disorders, and specifically ARVL, remains largely unknown (Frejo et al, 2016;Gallego-Martinez et al, 2018), and GWAS have not yet been performed to identify the genetic mechanisms contributing to ARVL.…”

A Missense Mutation in the KLF7 Gene Is a Potential Candidate Variant for Congenital Deafness in Australian Stumpy Tail Cattle Dogs

“…KLF7 was the nearby gene (50,519 bp distance) of one significant signal in adult hearing difficulty GWAS [ 52 ]. One recent GWAS of hearing-related traits with up to 330,759 individuals (UK Biobank) revealed 31 significant genomic risk loci for adult hearing difficulty, KLF7 was also detected to be significantly associated [ 53 ]. Furthermore, the protein sequence segments surrounding KLF7 variant are much more conserved than that of HEG1 among the same 7 species ( Figure 2 ).…”