Biological insights from multi-omic analysis of 31 genomic risk loci for adult hearing difficulty.
Biological insights from multi-omic analysis of 31 genomic risk loci for adult hearing difficulty.
复制标题
对成人听力难度的31个基因组风险基因座的多词分析的生物学见解。
DOI：
10.1371/journal.pgen.1009025
复制
发表时间：
2020-09
期刊：
影响因子：
4.5
通讯作者：
Ament SA
中科院分区：
文献类型：
--
作者：
Kalra G;Milon B;Casella AM;Herb BR;Humphries E;Song Y;Rose KP;Hertzano R;Ament SA
听力损失（ARHI）是最常见的疾病之一，具有很强的遗传性，但其遗传原因在很大程度上仍然未知。我们对英国生物库中多个听力相关性状的GWAS汇总统计数据进行了荟萃分析（n = 330，759），并确定了31个自我报告听力困难的全基因组显著风险位点（p <5x 10 -8），其中8个在同行评议文献中尚未报道。我们通过从小鼠耳蜗中的细胞产生mRNA-seq、ATAC-seq和单细胞RNA-seq来研究这些基因座的调控和细胞特异性表达。风险相关基因在耳蜗上皮细胞中表达最丰富，以及与感觉知觉相关的基因和已知的孟德尔耳聋基因，支持它们与听觉功能的相关性。与小鼠上皮细胞中开放染色质同源的人类基因组区域强烈富集听力困难的遗传风险，即使在调整了进化保守性和细胞类型非特异性调控区域的基线效应之后。表观基因组学和统计学精细定位最有力地支持50个推定的风险基因。其中，39个在小鼠耳蜗中强烈表达，16个在感觉毛细胞中特异性富集。这些结果揭示了听力困难的新的风险位点和风险基因，并建议改变耳蜗感觉上皮细胞的基因调控的重要作用。年龄相关性听力障碍（ARHI）是一种遗传性很强的疾病，其遗传结构尚未得到很好的研究。我们提出了ARHI风险基因座的系统遗传学分析。我们对来自英国生物库的四个听力相关特征进行了联合GWAS分析，并确定了31个听力困难的全基因组显著风险位点，其中8个以前没有报道过。通过整合这些风险基因座与转录组和表观基因组数据从小鼠耳蜗，我们发现，风险基因座强烈富集在基因和开放的染色质区域，是活跃在耳蜗感觉上皮细胞。我们的研究结果表明，在ARHI耳蜗毛细胞和支持细胞的基因调控改变的重要作用。
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. 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.
登录
查看更多内容
影响因子：
64.5
作者：
de la Torre-Ubieta L;Stein JL;Won H;Opland CK;Liang D;Lu D;Geschwind DH
通讯作者：
Geschwind DH
影响因子：
4.5
作者：
Hertzano R;Elkon R;Kurima K;Morrisson A;Chan SL;Sallin M;Biedlingmaier A;Darling DS;Griffith AJ;Eisenman DJ;Strome SE
通讯作者：
Strome SE
影响因子：
16.6
作者：
Burns JC;Kelly MC;Hoa M;Morell RJ;Kelley MW
通讯作者：
Kelley MW
遗传对人体组织基因表达的影响。
影响因子：
64.8
作者：
GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Lead analysts:;Laboratory, Data Analysis &Coordinating Center (LDACC):;NIH program management:;Biospecimen collection:;Pathology:;eQTL manuscript working group:;Battle A;Brown CD;Engelhardt BE;Montgomery SB
通讯作者：
Montgomery SB
影响因子：
9.8
作者：
Gusev, Alexander;Lee, S. Hong;Price, Alkes L.
通讯作者：
Price, Alkes L.