Burden of rare variants in synaptic genes in patients with severe tinnitus: An exome based extreme phenotype study.
Burden of rare variants in synaptic genes in patients with severe tinnitus: An exome based extreme phenotype study.
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DOI：
10.1016/j.ebiom.2021.103309
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发表时间：
2021-04
期刊：
影响因子：
11.1
通讯作者：
Lopez-Escamez JA
中科院分区：
文献类型：
--
作者：
Amanat S;Gallego-Martinez A;Sollini J;Perez-Carpena P;Espinosa-Sanchez JM;Aran I;Soto-Varela A;Batuecas-Caletrio A;Canlon B;May P;Cederroth CR;Lopez-Escamez JA
耳鸣是与听力和/或精神障碍相关的异质性病症。根据双胞胎、被收养者和家庭聚集研究，慢性、严重的耳鸣在1%的人口中报告，并显示出相关的遗传性。严重耳鸣的遗传贡献是未知的，因为大型基因组研究包括自我报告耳鸣和表型异质性大的个体。本研究的目的是鉴定极端表型患者中严重耳鸣的基因。对于这一极端表型研究，我们使用了三个不同的具有欧洲血统的组群（西班牙梅尼埃病（MD）、瑞典耳鸣和欧洲全身性癫痫）。此外，还使用了四个独立的对照数据集进行比较。对MD和癫痫队列进行全外显子组测序，对瑞典耳鸣患者进行全基因组测序。我们在西班牙队列中发现了24个突触基因中罕见的错义变体的富集，最显著的是PRUNE 2，AKAP 9，SORBS 1，ITGAX，ANK 2，KIF 20 B和TSC 2（p <2 E −04），当它们与参考数据集进行比较时。ANK 2基因的这种负担在97名耳鸣个体的瑞典队列中重复，并且在34名患有ANK 2，AKAP 9和TSC 2基因的严重耳鸣患者的子集中重复（p <2 E-02）。然而，在第三组701名无耳鸣的全身性癫痫患者中，这些相关性并不显著。基因本体论（GO）和基因集富集分析揭示了严重耳鸣中涉及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。ANK 2、AKAP 9和TSC 2中罕见变异的负担与严重耳鸣相关。ANK 2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。
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−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. 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.
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影响因子：
3
作者：
Guitton MJ
通讯作者：
Guitton MJ
影响因子：
3.9
作者：
Cederroth, Christopher R.;Lugo, Alessandra;Gallus, Silvano
通讯作者：
Gallus, Silvano
影响因子：
4.8
作者：
Mohler, PJ;Gramolini, AO;Bennett, V
通讯作者：
Bennett, V
IBS：用于生物序列呈现和可视化的插画家
DOI：
10.1093/bioinformatics/btv362
发表时间：
2015-10-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Liu W;Xie Y;Ma J;Luo X;Nie P;Zuo Z;Lahrmann U;Zhao Q;Zheng Y;Zhao Y;Xue Y;Ren J
通讯作者：
Ren J
影响因子：
13.6
作者：
Almqvist C;Adami HO;Franks PW;Groop L;Ingelsson E;Kere J;Lissner L;Litton JE;Maeurer M;Michaëlsson K;Palmgren J;Pershagen G;Ploner A;Sullivan PF;Tybring G;Pedersen NL
通讯作者：
Pedersen NL