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

Abstract

Background: Chronic age related dizziness arises from dysfunction of the balance system, an elegant neuroanatomical group of pathways that mediates our perception of linear acceleration, gravity, and angular head motion. Studies indicates that from 27 to 46% of chronic imbalance is genetically inherited, nevertheless, underlying genes leading to chronic imbalance remain unknown. Subjects and Methods: The population comprised diverse ancestry participants in the Million Veteran Program. Cases consisted of two diagnoses of dizziness at least six months apart, excluding acute vertiginous syndromes, ataxias, syncope, and traumatic brain injury. Genome-wide association studies were performed as separate logistic regressions on Europeans, Europeans of age ≥ 50, African Americans, and those of Hispanic ancestry, followed by transancestry metaanalysis. 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, LINC01225 - affecting transcription of ZNF91, a repressor of retrotransposons, and ROS1, a proto oncogene receptor tyrosine kinase. Discussion: Balance dysfunction can lead to catastrophic outcomes, including falls, injury, and death in the elderly. By honing the phenotype to be appropriate for chronic age related dizziness, findings suggest genomic candidates for further study and ultimate treatment of this common neurologic disease.