双侧前庭病与ZNF91/LINC01224位点的关联：一项全基因组关联研究

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中文摘要

背景与目的： 双侧前庭病（BVP）是一种由双侧外周前庭功能丧失引起的慢性疾病。尽管已确定若干病因，如耳毒性暴露、双侧梅尼埃病，以及近年来发现的单基因病因包括RFC1相关疾病和FGF14-GAA共济失调（SCA27B），但相当大比例的患者仍为特发性。
方法： 我们在一个欧洲队列中进行了全基因组关联研究（GWAS），该队列包括132例特发性BVP患者和3,410名未受影响的对照者。从患病个体中收集了临床和人口学数据。患者根据Bárány学会标准，通过视频头脉冲试验和/或冷热试验进行诊断。经过严格的质量控制和离群值剔除后，对约730万个插补变异进行了全基因组关联检验，随后进行了基于基因的和功能性的GWAS后分析，包括功能性变异注释、表达数量性状位点（eQTL）定位、染色质相互作用分析、基因集富集和调控基序注释。
结果： 2个位点上的3个变异达到了全基因组显著性。最强的关联出现在染色体19p12的ZNF91/LINC01224位点，包括位于LINC01224上游的rs12185481（p = 3.60E-16）和位于ZNF91内含子3内的rs8108073（p = 8.76E-12）。在染色体2q37.3上检测到第二个信号（rs73006457，p = 4.46E-08），该信号位于一个基因贫乏区域，最近的蛋白编码基因为GPC1和OTOS，两者均距离超过100 kb。基于基因的分析确定ZNF91具有显著关联。功能性注释优先确定了关键候选基因，并提示染色体19p12位点存在调控效应，包括跨脑区的eQTL信号——最显著的是在小脑中——以及与转录调控相关的基因集富集，并预测了转录因子结合基序的改变。
讨论： 本研究确定染色体19p12上的ZNF91/LINC01224位点是特发性BVP的主要遗传风险因素，提示在一个单一拓扑关联结构域内存在顺式调控机制，并对ZNF91表达产生下游影响。染色体2q37.3上的次要位点代表一个较不稳健的信号。这些发现需要在更大规模的独立队列中进行重复验证。

英文摘要

BACKGROUND AND OBJECTIVES: Bilateral vestibulopathy (BVP) is a chronic disorder resulting from bilateral loss of peripheral vestibular function. Although several etiologies have been identified, such as ototoxic exposure, bilateral Menière disease, and, more recently, monogenic causes including RFC1-related disorders and FGF14-GAA ataxia (SCA27B), a substantial proportion of cases remain idiopathic.
METHODS: We performed a genome-wide association study (GWAS) in a European cohort of 132 individuals with idiopathic BVP and 3,410 unaffected controls. Clinical and demographic data were collected from affected individuals. Patients were diagnosed according to the Bárány Society criteria using video head-impulse testing and/or caloric irrigation. After stringent quality control and outlier removal, genome-wide association testing was conducted on approximately 7.3 million imputed variants, followed by gene-based and functional post-GWAS analyses, including functional variant annotation, expression quantitative trait locus (eQTL) mapping, chromatin interaction analysis, gene-set enrichment, and regulatory motif annotation.
RESULTS: Three variants at 2 loci reached genome-wide significance. The strongest association was observed at the chromosome 19p12 ZNF91/LINC01224 locus, comprising rs12185481 located upstream of LINC01224 (p = 3.60E-16) and rs8108073 located within intron 3 of ZNF91 (p = 8.76E-12). A second signal was detected on chromosome 2q37.3 (rs73006457, p = 4.46E-08), located in a gene-poor region, with GPC1 and OTOS as the nearest protein-coding genes, both situated more than 100 kb away. Gene-based analysis identified ZNF91 as significantly associated. Functional annotation prioritized key candidate genes and indicated regulatory effects at the chromosome 19p12 locus, including eQTL signals across brain regions-most prominently in the cerebellum-as well as enrichment of gene sets related to transcriptional regulation, and predicted alterations of transcription factor binding motifs.
DISCUSSION: This study identifies the ZNF91/LINC01224 locus on chromosome 19p12 as a major genetic risk factor for idiopathic BVP, pointing to a cis-regulatory mechanism within a single topologically associating domain, with downstream effects on ZNF91 expression. The secondary locus on chromosome 2q37.3 represents a less robust signal. These findings warrant replication in larger, independent cohorts.