背景:耳鸣是一种与听力学和/或精神障碍相关的异质性疾病。慢性,据报道,1%的人口出现严重耳鸣,并显示出相关的遗传力,根据双胞胎的说法,被收养者和家庭聚集研究。严重耳鸣的遗传贡献是未知的,因为大型基因组研究包括具有自我报告的耳鸣和表型的大异质性的个体。这项研究的目的是鉴定具有极端表型的患者中严重耳鸣的基因。
方法:对于这个极端表型研究,我们使用了三个不同的欧洲血统的队列(西班牙梅尼埃病(MD),瑞典人耳鸣和欧洲广泛性癫痫)。此外,4个独立对照数据集也用于比较.对MD和癫痫队列进行全外显子组测序,并在有耳鸣的瑞典人中进行全基因组测序。
结果:我们在西班牙队列中的24个突触基因中发现了罕见的错义变异,最重要的是PRUNE2,AKAP9,SORBS1,ITGAX,ANK2、KIF20B和TSC2(p<2E-04),当它们与参考数据集进行比较时。ANK2基因的这种负担在瑞典有97名耳鸣个体的队列中被复制,在34例瑞典重度耳鸣患者中,ANK2,AKAP9和TSC2基因(p<2E-02)。然而,在701例无耳鸣的全身性癫痫患者的第三队列中,这些关联并不显著.基因本体论(GO)和基因集富集分析揭示了严重耳鸣的几种途径和生物学过程,包括神经元中的膜运输和细胞骨架蛋白结合。
结论:ANK2,AKAP9和TSC2中罕见变异的负担与严重耳鸣有关。ANK2编码一种细胞骨架支架蛋白,协调几种蛋白质的组装,驱动轴突分支并影响神经元的连通性。
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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-04), 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-02). 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.
CONCLUSIONS: 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.