Otology & Neurotology Group CTS495, Department of Genomic Medicine, GENYO-Centre for Genomics and Oncological Research-Pfizer/University of Granada/ Junta de Andalucía, PTS, Granada, Spain.
Hearing Sciences, Division of Clinical Neuroscience, School of Medicine, University of Nottingham, Nottingham, UK.
EBioMedicine. 2021 Apr;66:103309. doi: 10.1016/j.ebiom.2021.103309. Epub 2021 Apr 1.
tinnitus is a heterogeneous condition associated with audiological and/or mental disorders. Chronic, severe tinnitus is reported in 1% of the population and it shows a relevant heritability, according to twins, adoptees and familial aggregation studies. The genetic contribution to severe tinnitus is unknown since large genomic studies include individuals with self-reported tinnitus and large heterogeneity in the phenotype. The aim of this study was to identify genes for severe tinnitus in patients with extreme phenotype.
for this extreme phenotype study, we used three different cohorts with European ancestry (Spanish with Meniere disease (MD), Swedes tinnitus and European generalized epilepsy). In addition, four independent control datasets were also used for comparisons. Whole-exome sequencing was performed for the MD and epilepsy cohorts and whole-genome sequencing was carried out in Swedes with tinnitus.
we found an enrichment of rare missense variants in 24 synaptic genes in a Spanish cohort, the most significant being PRUNE2, AKAP9, SORBS1, ITGAX, ANK2, KIF20B and TSC2 (p < 2E), when they were compared with reference datasets. This burden was replicated for ANK2 gene in a Swedish cohort with 97 tinnitus individuals, and in a subset of 34 Swedish patients with severe tinnitus for ANK2, AKAP9 and TSC2 genes (p < 2E). However, these associations were not significant in a third cohort of 701 generalized epilepsy individuals without tinnitus. Gene ontology (GO) and gene-set enrichment analyses revealed several pathways and biological processes involved in severe tinnitus, including membrane trafficking and cytoskeletal protein binding in neurons.
a burden of rare variants in ANK2, AKAP9 and TSC2 is associated with severe tinnitus. ANK2, encodes a cytoskeleton scaffolding protein that coordinates the assembly of several proteins, drives axonal branching and influences connectivity in neurons.
耳鸣是一种与听力学和/或精神障碍相关的异质性疾病。据双胞胎、被领养者和家族聚集研究报告，慢性、严重的耳鸣在人群中的发病率为 1%，且具有显著的遗传性。由于大基因组研究包括有自我报告耳鸣的个体，并且表型存在很大的异质性，因此严重耳鸣的遗传贡献尚不清楚。本研究的目的是在具有极端表型的患者中鉴定严重耳鸣的相关基因。
在这项极端表型研究中，我们使用了三个具有欧洲血统的队列（西班牙梅尼埃病患者、瑞典耳鸣患者和欧洲泛发性癫痫患者）。此外，还使用了四个独立的对照数据集进行比较。对梅尼埃病和癫痫队列进行全外显子测序，对瑞典耳鸣患者进行全基因组测序。
与参考数据集相比，我们在西班牙队列中发现 24 个突触基因中的罕见错义变异明显富集，最显著的是 PRUNE2、AKAP9、SORBS1、ITGAX、ANK2、KIF20B 和 TSC2（p < 2E）。在瑞典的 97 名耳鸣患者和瑞典的 34 名严重耳鸣患者亚组中，ANK2 基因也复制了这种负担，对于 AKAP9 和 TSC2 基因也是如此（p < 2E）。然而，在没有耳鸣的 701 名泛发性癫痫患者的第三个队列中，这些关联并不显著。基因本体（GO）和基因集富集分析显示，几个涉及严重耳鸣的通路和生物过程，包括神经元中的膜转运和细胞骨架蛋白结合。
ANK2、AKAP9 和 TSC2 中的罕见变异负担与严重耳鸣相关。ANK2 编码一种细胞骨架支架蛋白，它协调几种蛋白质的组装，驱动轴突分支，并影响神经元的连接。
