Table 3.
Discovery and mega rare-variant aggregate association analysis with age-related hearing loss traits.
| Sample | Type of variation | Gene | H-aid | H-diff | H-noise | H-both | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Beta (OR) | SE | P | Beta (OR) | SE | P | Beta (OR) | SE | P | Beta (OR) | SE | P | |||
| Discovery | pLoF | KLHDC7B | 1.29 (3.6) | 0.21 | 2.65 × 10−8 | 0.69 (1.9) | 0.12 | 5.59 × 10−9 | 0.56 (1.8) | 0.11 | 2.01 × 10−7 | 0.77 (2.2) | 0.12 | 3.99 × 10−10 |
| TECTA | 0.84 (2.3) | 0.16 | 7.08 × 10−8 | 0.84 (2.3) | 0.16 | 4.18 × 10−7 | ||||||||
| EYA4 | 3.30 (27.1) | 0.61 | 1.74 × 10−6 | |||||||||||
| pLoF + missense | PDCD6 | 1.06 (2.9) | 0.15 | 1.57 × 10−10 | 0.67 (2.0) | 0.08 | 6.22 × 10−17 | 0.50 (1.7) | 0.07 | 1.08 × 10−11 | 0.69 (2.0) | 0.08 | 4.07 × 10−16 | |
| PDCD6a | 0.76 (2.1) | 0.19 | 1.33 × 10−4 | 0.45 (1.6) | 0.09 | 1.07 × 10−6 | 0.34 (1.4) | 0.08 | 4.27 × 10−5 | 0.50 (1.7) | 0.10 | 2.26 × 10−7 | ||
| MYO6 | 0.44 (1.6) | 0.08 | 4.54 × 10−7 | |||||||||||
| MYO6b | 0.40 (1.5) | 0.08 | 7.30 × 10−6 | |||||||||||
| Mega | pLoF | KLHDC7B | 1.10 (3.0) | 0.20 | 6.23 × 10−7 | 0.71 (2.0) | 0.10 | 1.55 × 10−11 | 0.56 (1.8) | 0.10 | 5.72 × 10−9 | 0.77 (2.2) | 0.11 | 1.73 × 10−12 |
| TECTA | 0.85 (2.3) | 0.14 | 1.09 × 10−9 | 0.66 (1.9) | 0.13 | 5.86 × 10−7 | 0.83 (2.3) | 0.15 | 2.26 × 10−8 | |||||
| MYO6 | 1.43 (4.2) | 0.25 | 4.67 × 10−7 | |||||||||||
| GJB2 | 0.21 (1.2) | 0.04 | 1.77 × 10−6 | |||||||||||
| GJB2c | 0.11 (1.1) | 0.14 | 4.3 × 10−1 | |||||||||||
| pLoF + missense | PDCD6 | 1.03 (2.8) | 0.13 | 5.41×10−13 | 0.66 (1.9) | 0.07 | 1.93 × 10−21 | 0.49 (1.6) | 0.06 | 1.99 × 10−14 | 0.68 (2.0) | 0.07 | 5.38 × 10−21 | |
| PDCD6a | 0.78 (2.2) | 0.16 | 4.94 × 10−6 | 0.43 (1.1) | 0.08 | 6.53 × 10−8 | 0.32 (1.4) | 0.07 | 1.89 × 10−5 | 0.48 (1.6) | 0.08 | 8.69 × 10−9 | ||
| MYO6 | 0.43 (1.5) | 0.07 | 5.20 × 10−9 | |||||||||||
| MYO6b | 0.38 (1.5) | 0.07 | 2.45 × 10−7 | |||||||||||
| PUS7L | −0.34 (0.7) | 0.07 | 3.85 × 10−7 | |||||||||||
| GJB2 | 0.15 (1.2) | 0.03 | 6.42 × 10−8 | 0.17 (1.2) | 0.03 | 3.50 × 10−8 | ||||||||
| GJB2c | 0.11 (1.1) | 0.03 | 1.60 × 10−3 | 0.13 (1.4) | 0.04 | 4.40 × 10−4 | ||||||||
Genes associated to an exome-wide significance level (p < 2.5 × 10−6) with hearing aid (H-aid), hearing difficulty (H-diff), hearing difficulty with background noise (H-noise), and the combined trait (H-both). Using rare-variant aggregate association tests pLoF or missense + pLoF variants with a MAF < 0.01 in gnomAD v2.1.1 were analyzed in the discovery and mega-samples of white-European individuals from the UK Biobank. The p-values for replicated associations [empirical p-values <0.05 adjusting for genes (pLoF and missense & pLof) and traits brought to replication], are shown in bold (See Table S6 for replication analytical and empirical values).
pLoF putative loss of function, CHR chromosome, EA effect allele, EAF effect allele frequency, OR odds ratio, SE standard error, P p-value.
aResults when variants: rs549592074 and rs571370281 in PDCD6 were removed.
bResults when rs121912560 in MYO6 was removed.
cResults when rs80338939 in GJB2 was removed.