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Genome-Wide Association Study of Chronic Dizziness in the Elderly Identifies Loci Implicating MLLT10, BPTF, LINC01224, and ROS1.

Publication ,  Journal Article
Clifford, R; Munro, D; Dochtermann, D; Devineni, P; Pyarajan, S; Million Veteran Program, ; Telese, F; Palmer, AA; Mohammadi, P; Friedman, R
Published in: J Assoc Res Otolaryngol
December 2023

PURPOSE: Chronic age-related imbalance is a common cause of falls and subsequent death in the elderly and can arise from dysfunction of the vestibular system, an elegant neuroanatomical group of pathways that mediates human perception of acceleration, gravity, and angular head motion. Studies indicate that 27-46% of the risk of age-related chronic imbalance is genetic; nevertheless, the underlying genes remain unknown. METHODS: The cohort consisted of 50,339 cases and 366,900 controls in the Million Veteran Program. The phenotype comprised cases with two ICD diagnoses of vertigo or dizziness at least 6 months apart, excluding acute or recurrent vertiginous syndromes and other non-vestibular disorders. Genome-wide association studies were performed as individual logistic regressions on European, African American, and Hispanic ancestries 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: Two significant loci were identified in Europeans, another in the Hispanic population, and two additional in trans-ancestry meta-analysis, including three novel loci. Fine mapping revealed credible sets of intronic single nucleotide polymorphisms (SNPs) in MLLT10 - a histone methyl transferase cofactor, BPTF - a subunit of a nucleosome remodeling complex implicated in neurodevelopment, and LINC01224 - a proto-oncogene receptor tyrosine kinase. CONCLUSION: Despite the difficulties of phenotyping the nature of chronic imbalance, we replicated two loci from previous vertigo GWAS studies and identified three novel loci. Findings suggest candidates for further study and ultimate treatment of this common elderly disorder.

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Published In

J Assoc Res Otolaryngol

DOI

EISSN

1438-7573

Publication Date

December 2023

Volume

24

Issue

6

Start / End Page

575 / 591

Location

United States

Related Subject Headings

  • Vertigo
  • Transcription Factors
  • Proto-Oncogene Proteins
  • Protein-Tyrosine Kinases
  • Polymorphism, Single Nucleotide
  • Otorhinolaryngology
  • Humans
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
  • Dizziness
 

Citation

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Clifford, R., Munro, D., Dochtermann, D., Devineni, P., Pyarajan, S., Million Veteran Program, ., … Friedman, R. (2023). Genome-Wide Association Study of Chronic Dizziness in the Elderly Identifies Loci Implicating MLLT10, BPTF, LINC01224, and ROS1. J Assoc Res Otolaryngol, 24(6), 575–591. https://doi.org/10.1007/s10162-023-00917-y
Clifford, Royce, Daniel Munro, Daniel Dochtermann, Poornima Devineni, Saiju Pyarajan, Saiju Million Veteran Program, Francesca Telese, Abraham A. Palmer, Pejman Mohammadi, and Rick Friedman. “Genome-Wide Association Study of Chronic Dizziness in the Elderly Identifies Loci Implicating MLLT10, BPTF, LINC01224, and ROS1.J Assoc Res Otolaryngol 24, no. 6 (December 2023): 575–91. https://doi.org/10.1007/s10162-023-00917-y.
Clifford R, Munro D, Dochtermann D, Devineni P, Pyarajan S, Million Veteran Program, et al. Genome-Wide Association Study of Chronic Dizziness in the Elderly Identifies Loci Implicating MLLT10, BPTF, LINC01224, and ROS1. J Assoc Res Otolaryngol. 2023 Dec;24(6):575–91.
Clifford, Royce, et al. “Genome-Wide Association Study of Chronic Dizziness in the Elderly Identifies Loci Implicating MLLT10, BPTF, LINC01224, and ROS1.J Assoc Res Otolaryngol, vol. 24, no. 6, Dec. 2023, pp. 575–91. Pubmed, doi:10.1007/s10162-023-00917-y.
Clifford R, Munro D, Dochtermann D, Devineni P, Pyarajan S, Million Veteran Program, Telese F, Palmer AA, Mohammadi P, Friedman R. Genome-Wide Association Study of Chronic Dizziness in the Elderly Identifies Loci Implicating MLLT10, BPTF, LINC01224, and ROS1. J Assoc Res Otolaryngol. 2023 Dec;24(6):575–591.
Journal cover image

Published In

J Assoc Res Otolaryngol

DOI

EISSN

1438-7573

Publication Date

December 2023

Volume

24

Issue

6

Start / End Page

575 / 591

Location

United States

Related Subject Headings

  • Vertigo
  • Transcription Factors
  • Proto-Oncogene Proteins
  • Protein-Tyrosine Kinases
  • Polymorphism, Single Nucleotide
  • Otorhinolaryngology
  • Humans
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
  • Dizziness