GWAS of Chronic Dizziness in the Elderly Identifies Novel Loci ImplicatingMLLT10, BPTF, LINC01225, andROS1

Abstract

ABSTRACTBackgroundChronic 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.MethodsThe 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.ResultsThe 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 includingMLLT10- a histone methyl transferase cofactor,BPTF- a subunit of a nucleosome remodeling complex implicated in neurodevelopment,LINC01224- affecting transcription ofZNF91, a repressor of retrotransposons, andROS1– a proto-oncogene receptor tyrosine kinase.ConclusionBalance 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.KEY MESSAGESWhat is already known on this topicThe 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 addsIn 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 policyAscertaining 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.