GWAS of Chronic Dizziness in the Elderly Identifies Novel Loci Implicating MLLT10, BPTF, LINC01225, and ROS1

Background Chronic age-related dizziness can arise from dysfunction of the vestibulocochlear system, an elegant neuroanatomical group of pathways that mediates human perception of linear acceleration, gravity, and angular head motion. Studies indicates that 27-46% of chronic imbalance is genetically inherited, nevertheless, underlying genes leading to chronic imbalance remain unknown. Methods The Million Veteran Program comprises over 900,000 diverse-ancestry participants. Cases required two diagnoses of dizziness at least six months apart, excluding acute vertiginous syndromes, ataxias, syncope, and traumatic brain injury. Genome-wide association studies (GWAS’) were performed as separate logistic regressions on Europeans, African Americans, and those of Hispanic ancestry, followed by trans-ancestry meta-analysis. Downstream analysis included case-case-GWAS, fine-mapping, probabilistic colocalization of significant variants and genes with eQTLs, and functional analysis of significant hits. Results The final cohort consisted of 50,339 cases and 366,900 controls. Two significant loci were identified in Europeans, another in the Hispanic population, and two additional loci in trans-ancestry meta-analysis. Fine mapping revealed credible sets of intronic single nucleotide polymorphisms in genes including MLLT10 - a histone methyl transferase cofactor, BPTF - a subunit of a nucleosome remodeling complex implicated in neurodevelopment, LINC01224 - affecting transcription of ZNF91 , a repressor of retrotransposons, and ROS1 – a proto-oncogene receptor tyrosine kinase. Conclusion Balance dysfunction can lead to catastrophic outcomes, including falls, injury, and death in the elderly. By removing acute vertiginous syndromes and non-cochlear disorders to focus on vestibulocochlear age-related dizziness, findings suggest genomic candidates for further study and ultimate treatment of this common neurologic disease. What is already known on this topic The vestibule of the cochlea is a neuroanatomic structure mediating balance, and chronic imbalance in the elderly is a large predictor of falls and their associated morbidities and mortalities. Chronic vestibular balance is 27% - 46% heritable, however, underlying genes are unknown. What this study adds In a genome-wide association study, we identified novel single nucleotide polymorphisms and genes associated with chronic dizziness in the elderly. How this study might affect research, practice or policy Ascertaining the physiologic/genetic architecture in the cochleovestibular system will aid in future treatment where drug development can target specifically genes related to imbalance. Individuals at higher genetic risk for imbalance can be provided more focused preventive vestibular therapy. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by NIH Grant #R01 DC020052-02 and VA RR&D Award 5I01RX002744-04. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Prior written informed consent for use of health records and genomic data was obtained for all participants in this retrospective analysis within the Million Veteran Program. This study was approved by Central Veterans Administration IRB reference E22-36, qualifying for exemption under category 4(ii). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the Million Veteran Program, and will be available at dbGap upon approval for publication in a peer-reviewed journal.