Compare genetic associations and heritability estimates from quantitative audiometric measurements with those from diagnostic codes for sensorineural hearing loss.
Approach:
Study design: Researchers conducted two genome-wide association studies using whole-genome sequencing data from Vanderbilt’s BioVU biobank. Both analyses included participants of European genetic ancestry.
Phenotyping: The diagnostic-code analysis included 61,468 participants (10,164 cases and 51,304 controls). The audiometry analysis included 16,057 participants and used a continuous three-frequency pure-tone average from the better-hearing ear.
Validation: Researchers assessed genetic correlations with hearing-related traits and tested polygenic risk scores in 109,096 participants from the All of Us Research Program.
Key Findings:
The audiometry-based GWAS identified three genome-wide significant loci, functionally mapped to four genes: EML6, SPTBN1, ARHGEF28, and EYA4; the diagnostic-code analysis identified none.
The audiometry analysis found 41 suggestive loci, compared with 21 in the diagnostic-code analysis.
Estimated single-nucleotide variant heritability was 11.8% for audiometry and 2.9% for diagnostic codes. Among 7,479 participants in both cohorts, diagnostic codes and PTA measurements were weakly correlated.
Audiometry-based genetic results showed significant genetic correlations with several hearing-related traits. The strongest reported genetic correlation was with hearing aid use (r = 0.985); no significant genetic correlation was found with speech recognition in noise.
In All of Us, each 1-standard-deviation increase in the PTA-derived polygenic risk score was associated with 9% higher odds of self-reported deafness or serious hearing difficulty. The diagnostic-code-derived score showed no corresponding association; the authors described the association as modest.
Interpretation:
The authors suggested that quantitative audiometric phenotyping may improve detection of genetic signals associated with hearing sensitivity. They noted that the observed polygenic risk score association was modest and that its clinical predictive value remains unproven.
Limitations:
The primary analyses included only participants of European genetic ancestry.
Audiometry was represented by a single three-frequency average from the better-hearing ear, which may not capture frequency-specific or between-ear differences.
Differences in age definitions between cohorts may have introduced bias.
Validation used a single self-reported question focused on deafness or serious hearing difficulty, potentially missing milder hearing loss.
Conclusion:
The authors called for larger, more diverse cohorts with detailed audiometric measurements to validate the findings and improve risk estimation.
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