生物
遗传学
全基因组关联研究
表观遗传学
基因
耳蜗
数量性状位点
基因表达
单核苷酸多态性
神经科学
DNA甲基化
基因型
作者
Gurmannat Kalra,Béatrice Milon,Alex M. Casella,Brian R. Herb,Elizabeth Humphries,Yang Song,Kevin Rose,Ronna Hertzano,Seth A. Ament
出处
期刊:PLOS Genetics
日期:2020-09-28
卷期号:16 (9): e1009025-e1009025
被引量:56
标识
DOI:10.1371/journal.pgen.1009025
摘要
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.
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