The three most significantly associated SNPs for hearing loss are all located at the GJB2/GJB6 locus on 13q12.1 (Figure 8), including rs870729 near GJB6 (p = 3.38×10−11, OR: 1.69), rs3751385 within GJB2 (p = 1.50×10−9, OR: 1.63), and rs7329467 within GJA3 (p = 6.87×10−8, OR: 1.68). The three SNPs have weak LD with each other (pairwise r 2 values range from 0.02 to 0.62), but all of them are common variants. For example, rs870729 has a minor allele frequency (MAF) of 18.7% in controls and 28.0% in cases. To evaluate the independence of the association signals from the three SNPs, we tested association again by incorporating rs870729 in a logistic regression model, yet still found residual association for rs7329467 (p = 4.3×10−6), but not rs3751385 (p = 0.33), consistent with the expectations derived above for the behavior of synthetic associations. The locus has been extensively resequenced in numerous studies, and there is no common causal variant at the locus with ∼18.7% allele frequency similar to rs870729. Therefore, rare variants at the locus create multiple independent association signals captured by common tagging SNPs.
