Polygenic Risk Scores and Hearing Loss Phenotypes in Children.

IMPORTANCE

Monogenic causes of childhood hearing loss are well established, as are polygenic risk contributions to age-related hearing loss. However, an untested possibility is that polygenic risk scores (PRS) also contribute to childhood hearing loss of all severities, alongside environmental and/or monogenic causes.

OBJECTIVE

To examine the association between a PRS for adult hearing loss and childhood hearing loss phenotypes.

DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study used a unique population-based dataset spanning normal hearing to profound loss, combining 2 contemporaneous population cohorts in Australia. This included the Child Health CheckPoint, a national population-based cross-sectional study nested within the Longitudinal Study of Australian Children, and the Victorian Childhood Hearing Longitudinal Databank (VicCHILD), a statewide population-based longitudinal data bank open to every child with congenital hearing loss in Victoria, Australia. The analysis took place from March to August 2023.

EXPOSURES

Genotype data were generated from saliva- or blood-derived DNA using global single-nucleotide variations arrays. Based on genotype data, PRS was computed using published UK Biobank genome-wide association study results for self-reported hearing difficulty in individuals aged 40 to 69 years.

MAIN OUTCOMES AND MEASURES

Hearing outcomes were classified by laterality (bilateral, unilateral), severity (mild, moderate, severe or worse) and types (sensorineural, conductive, mixed, auditory neuropathy, atresia). Analyses included multinominal logistic regressions of PRS with hearing outcomes.

RESULTS

Overall, 1488 CheckPoint study children (49.8% boys, aged 11-12 years) and 527 VicCHILD study children (55.2% boys, aged 0-13 years) with hearing and genotype data were included. A 1-SD increment in PRS was associated with higher odds of mild (odds ratio [OR], 1.3; 95% CI, 1.0-1.6), moderate (OR, 5.1; 95% CI, 3.2-8.1), and severe or worse (OR, 5.3; 95% CI, 3.9-7.3) unilateral hearing loss compared with normal hearing. Similarly, the PRS was associated with increased odds of mild, moderate, and severe or worse bilateral hearing loss (per-SD ORs, 3.9-6.6) and all hearing loss types (per-SD ORs, 8.5-10.6).

CONCLUSIONS AND RELEVANCE

In this cross-sectional study, a PRS initially developed for adult hearing difficulty was associated with wide-ranging childhood hearing loss phenotypes, partly explaining hearing phenotype variations despite shared genetic and environmental factors (eg, preterm birth). Large-scale studies with objectively defined hearing phenotypes are crucial for refining PRS and predicting high-risk children.