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

Autoři: Gurmannat Kalra aff001;  Beatrice Milon aff003;  Alex M. Casella aff001;  Brian R. Herb aff001;  Elizabeth Humphries aff001;  Yang Song aff001;  Kevin P. Rose aff001;  Ronna Hertzano aff001;  Seth A. Ament aff001;  Kevin P. Rose aff002
Působiště autorů: Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, United States of America aff001;  Program in Molecular Medicine, University of Maryland School of Medicine, Baltimore, MD, United States of America aff002;  Department of Otorhinolaryngology-Head & Neck Surgery, University of Maryland School of Medicine, Baltimore, MD, United States of America aff003;  Physician Scientist Training Program, University of Maryland School of Medicine, Baltimore, MD, United States of America aff004;  Program in Molecular Epidemiology, University of Maryland School of Medicine, Baltimore, MD, United States of America aff005;  Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, United States of America aff006;  Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, United States of America aff007
Vyšlo v časopise: Biological insights from multi-omic analysis of 31 genomic risk loci for adult hearing difficulty. PLoS Genet 16(9): e32767. doi:10.1371/journal.pgen.1009025
Kategorie: Research Article
doi: 10.1371/journal.pgen.1009025


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 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.

Klíčová slova:

Cochlea – Deafness – Gene regulation – Genetic loci – Genome-wide association studies – Chromatin – Medical risk factors – Single nucleotide polymorphisms – Mammalian genomics


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