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

Author summary The genetic architecture of age-related hearing impairment (ARHI), a strongly heritable condition, has not been well studied. We present a systems genetics analysis of risk loci for ARHI. We performed a joint GWAS analysis of four hearing related traits from the UK Biobank and identified 31 genome-wide significant risk loci for hearing difficulty, eight of which have not been previously reported. By integrating these risk loci with transcriptomic and epigenomic data from the mouse cochlea, we discovered that risk loci are strongly enriched at genes and open chromatin regions that are active in cochlear sensory epithelial cells. Our results suggest an important role in ARHI for altered gene regulation in cochlear hair cells and supporting cells. 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 meta-analysis 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 peer-reviewed 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 sensory 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 fine-mapping 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.