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

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    Author
    Kalra, Gurmannat
    Milon, Beatrice
    Casella, Alex M
    Herb, Brian R
    Humphries, Elizabeth
    Song, Yang
    Rose, Kevin P
    Hertzano, Ronna
    Ament, Seth A
    Date
    2020-09-28
    Journal
    PLoS genetics
    Publisher
    Public Library of Science
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1371/journal.pgen.1009025
    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 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.
    Sponsors
    This project was supported by National Institute of Mental Health, BRAIN Initiative (R24 MH114815, R.H.)
    Keyword
    age-related hearing impairment
    Genetic Loci
    Hearing Loss-genetics
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/13889
    ae974a485f413a2113503eed53cd6c53
    10.1371/journal.pgen.1009025
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