Biological insights from multi-omic analysis of 31 genomic risk loci for adult hearing difficulty.
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...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2020-09-01
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| Series: | PLoS Genetics |
| Online Access: | https://doi.org/10.1371/journal.pgen.1009025 |
| _version_ | 1811160739961896960 |
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| author | Gurmannat Kalra Beatrice Milon Alex M Casella Brian R Herb Elizabeth Humphries Yang Song Kevin P Rose Ronna Hertzano Seth A Ament |
| author_facet | Gurmannat Kalra Beatrice Milon Alex M Casella Brian R Herb Elizabeth Humphries Yang Song Kevin P Rose Ronna Hertzano Seth A Ament |
| author_sort | Gurmannat Kalra |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-10T06:03:42Z |
| format | Article |
| id | doaj.art-4350f231662f4972a40dd8d76fb52664 |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-04-10T06:03:42Z |
| publishDate | 2020-09-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS Genetics |
| spelling | doaj.art-4350f231662f4972a40dd8d76fb526642023-03-03T05:31:19ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042020-09-01169e100902510.1371/journal.pgen.1009025Biological insights from multi-omic analysis of 31 genomic risk loci for adult hearing difficulty.Gurmannat KalraBeatrice MilonAlex M CasellaBrian R HerbElizabeth HumphriesYang SongKevin P RoseRonna HertzanoSeth A AmentAge-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.https://doi.org/10.1371/journal.pgen.1009025 |
| spellingShingle | Gurmannat Kalra Beatrice Milon Alex M Casella Brian R Herb Elizabeth Humphries Yang Song Kevin P Rose Ronna Hertzano Seth A Ament Biological insights from multi-omic analysis of 31 genomic risk loci for adult hearing difficulty. PLoS Genetics |
| title | Biological insights from multi-omic analysis of 31 genomic risk loci for adult hearing difficulty. |
| title_full | Biological insights from multi-omic analysis of 31 genomic risk loci for adult hearing difficulty. |
| title_fullStr | Biological insights from multi-omic analysis of 31 genomic risk loci for adult hearing difficulty. |
| title_full_unstemmed | Biological insights from multi-omic analysis of 31 genomic risk loci for adult hearing difficulty. |
| title_short | Biological insights from multi-omic analysis of 31 genomic risk loci for adult hearing difficulty. |
| title_sort | biological insights from multi omic analysis of 31 genomic risk loci for adult hearing difficulty |
| url | https://doi.org/10.1371/journal.pgen.1009025 |
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