Association of Bilateral Vestibulopathy With the ZNF91/LINC01224 Locus: A Genome-Wide Association Study

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.

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.

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.

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.