Genetic predisposition to tinnitus in the UK Biobank population.
Genetic predisposition to tinnitus in the UK Biobank population.
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DOI：
10.1038/s41598-021-97350-z
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发表时间：
2021-09-13
影响因子：
4.6
通讯作者：
Zuo J
中科院分区：
文献类型：
--
作者：
Urbanek ME;Zuo J
耳鸣是一种源自内耳的噪音幻觉，据报道，世界上15%的人口患有耳鸣，许多患者报告存在认知和情绪方面的严重缺陷。然而，客观的诊断工具和有针对性的治疗策略尚未建立。为了更好地了解可能阻止耳鸣的潜在基因，我们对英国生物银行49,960名全外显子组测序参与者进行了全基因组关联研究，以确定任何与耳鸣强烈相关的位点。我们在两个性别分开的报告慢性、令人困扰的耳鸣的队列中发现了17个暗含的单核苷酸多态性（p < 1e−5），跨越13个基因（对照男性n = 7,315，耳鸣男性n = 226，对照女性n = 11,732，耳鸣女性n = 300）。我们还在女性队列中发现了一个显著的WDPCP错义突变（p = 3.959e−10），该突变先前涉及通过轴突迁移和结构强化的典型神经元功能，以及Bardet-Biedl综合征-15（一种纤毛病）。此外，胚胎和P56小鼠大脑的原位杂交表明，这些基因中的大多数在耳蜗背核中表达，该区域被认为是最初诱导耳鸣的大脑区域。进一步的RT-qPCR和RNAScope数据也揭示了这种表达模式。这项研究的结果表明，耳鸣的易感性可能跨越多个基因组位点，并由耳蜗背核内的神经回路减弱和不适应的细胞骨架修饰建立。
Tinnitus, the phantom perception of noise originating from the inner ear, has been reported by 15% of the world’s population, with many patients reporting major deficits to cognition and mood. However, both objective diagnostic tools and targeted therapeutic strategies have yet to be established. To better understand the underlying genes that may preclude tinnitus, we performed a genome-wide association study of the UK Biobank’s 49,960 whole exome sequencing participants to identify any loci strongly associated with tinnitus. We identified 17 suggestive single nucleotide polymorphisms (p < 1e−5) spanning 13 genes in two sex-separated cohorts reporting chronic, bothersome tinnitus (control males n = 7,315, tinnitus males n = 226, control females n = 11,732, tinnitus females n = 300). We also found a significant missense mutation in WDPCP (p = 3.959e−10) in the female cohort, a mutation which has been previously implicated in typical neuronal functioning through axonal migration and structural reinforcement, as well as in Bardet-Biedl syndrome-15, a ciliopathy. Additionally, in situ hybridization in the embryonic and P56 mouse brain demonstrated that the majority of these genes are expressed within the dorsal cochlear nucleus, the region of the brain theorized to initially induce tinnitus. Further RT-qPCR and RNAScope data also reveals this expression pattern. The results of this study indicate that predisposition to tinnitus may span across multiple genomic loci and be established by weakened neuronal circuitry and maladaptive cytoskeletal modifications within the dorsal cochlear nucleus.
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影响因子：
3.7
作者：
Bai Y;Wang D;Li W;Huang Y;Ye X;Waite J;Barry T;Edelmann KH;Levenkova N;Guo C;Skokos D;Wei Y;Macdonald LE;Fury W
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