Clinical Scorecard: Audiometry-based GWAS identifies 3 genome-wide significant hearing-sensitivity loci

At a Glance

Key Highlights

• The audiometry-based GWAS included 16,057 participants and identified 3 genome-wide significant loci, functionally annotated to EML6, SPTBN1, ARHGEF28, and EYA4.
• The diagnostic-code GWAS included 61,468 participants and identified no genome-wide significant loci; it identified 21 suggestive loci, compared with 41 in the audiometry-based analysis.
• Estimated single-nucleotide variant–based heritability was 11.8% for the PTA-based analysis and 2.9% for the diagnostic-code analysis.
• In the independent All of Us cohort, each 1-standard-deviation increase in the PTA-derived polygenic risk score was associated with statistically significant, 9% higher odds of self-reported deafness or serious hearing difficulty; diagnostic-code-derived scores showed no corresponding association. The authors described the association as modest.
• The authors stated that the polygenic risk scores' usefulness for predicting hearing loss in individual patients remains unproven.

Guideline-Based Recommendations

Diagnosis

• The study compared medical-record diagnostic codes with continuous 3-frequency pure-tone averages at 500, 1,000, and 2,000 Hz from the better-hearing ear; it did not provide clinical diagnostic guidelines.

Management

• The article reports no treatment or management recommendations.

Monitoring & Follow-up

• The article provides no clinical monitoring recommendations. The authors called for larger, more diverse cohorts with detailed audiometric measurements to validate the findings and improve risk estimation.

Risks

• The primary genetic analyses included only participants of European genetic ancestry, limiting generalizability to other populations.
• A single 3-frequency average from the better-hearing ear may not capture frequency-specific or between-ear differences.
• The independent validation used a single self-reported question focused on deafness or serious hearing difficulty and may not capture milder hearing loss.
• The authors cautioned that the clinical predictive value of the current polygenic risk scores remains unproven.

Patient & Prescribing Data

The BioVU diagnostic-code cohort included 10,164 participants with sensorineural hearing loss and 51,304 controls; the audiometry cohort included 16,057 participants. Both primary cohorts were restricted to European genetic ancestry. The independent All of Us cohort included 109,096 participants.

No treatment or prescribing data were reported. In the validation cohort, 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; individual-level predictive usefulness remains unproven.

Clinical Best Practices

• The study's PTA phenotype was a 3-frequency average from the better-hearing ear; the authors noted that this may overlook frequency-specific or between-ear differences.
• The primary analyses were restricted to European genetic ancestry, and the authors called for validation in larger, more diverse cohorts.
• The authors stated that the current polygenic risk scores' clinical predictive value remains unproven.

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