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Vertigo Risk Variant Set Points to Related Inner Ear Processes


NEW YORK – A team led by investigators at Amgen subsidiary Decode Genetics has tracked down half a dozen genetic loci linked to vertigo in individuals with European ancestry — a set that included variants in genes involved in inner ear development and other vertigo-related processes.

"Vertigo is the disturbing illusion of motion, most commonly rotational motion, of oneself or the environment," first and co-corresponding author Astros Skuladottir, a researcher with Decode, and her co-authors wrote in Communications Biology on Thursday, noting that the condition "is a major risk factor for falls and bone fractures, placing a great burden on the healthcare system."

Such symptoms can arise from a range of pathophysiological causes that impact the so-called vestibular system in the inner ear, they explained, which is involved in sensing motion and direction. But while at least some of the conditions that have a central or peripheral effect on this vestibular system can become more common with age or cluster in certain families or populations, the genetic underpinnings of vertigo are poorly understood.

For the current study, the researchers sought out vertigo contributors with a genome-wide association study and GWAS meta-analysis that included more than 48,000 individuals with vertigo from Iceland, the UK, the US, and Finland and nearly 895,000 unaffected control individuals from the same populations.

Based on medical record diagnostic code clues and array-based genotypes for the cases and controls, which were fleshed out with Decode's Icelandic whole-genome sequence data, the team scrutinized more than 62 million variants across the genome, identifying significant ties to vertigo at common variant sites in or near the ZNF91, TECTA, OTOG, OTOGL, ARMC9, and OTOP1 genes.

"Our results uncovered sequence variants associating with vertigo in a genome-wide association study," the authors reported, "and implicated genes with known roles in inner ear development, maintenance, and disease."

Data from the GTEx project and available RNA sequences on blood or fat tissue samples from up to 13,175 individuals in Iceland hinted that the vertigo risk variant near ARMC9 may be part of an expression quantitative trait locus (or eQTL linkage group) influencing the gene's activity in adipose and other tissue types.

A missense variant in ZNF91 had the strongest vertigo associations in Iceland and the UK, the authors reported, noting that the variant was in linkage disequilibrium with a brain tissue eQTL for the LINC01224 genes. At the TECTA locus, a missense variant appeared to have distinct directional effects on vertigo risk in the Finnish cohort compared to participants from Iceland, the UK, and the US.

The researchers did not detect genetic overlap between the vertigo-associated variants at these loci and variants previously implicated in general hearing loss, though the TECTA gene risk variant seemed to have at least subtle effects on age-related hearing loss in an analysis that included participants from the UK and Iceland. And still other suspicious variants turned up when they interrogated parts of the genome that were previously linked to vertigo-related conditions such as age-related hearing impairment or motion sickness.

With a gene-based analysis, meanwhile, the team found that variants in nearly three-dozen genes were overrepresented in the individuals with vertigo. It also started teasing out genetic contributors to specific vertigo subtypes using GWAS data, along with insights from additional German cohorts, unearthing an outsized role for risk variants at the ZNF91, OTOGL, and OTOP1 loci in a form of the condition called benign paroxysmal positional vertigo.

"Our study unveiled genome-wide significant associations with vertigo and revealed sequence variants in genes that may contribute to the pathogenesis of diseases in either the auditory system or the vestibular system," the authors wrote, adding that "the results further our understanding of the biological underpinnings of the vestibular and auditory systems."