Correction: Genome-Wide Association Study Identifies Nox3 as a Critical Gene for Susceptibility to Noise-Induced Hearing Loss

Abstract Background Tinnitus is an auditory phantom sensation in the absence of an acoustic stimulus, which affects nearly 15% of the population. Excessive noise exposure is one of the main causes of tinnitus. To now, the knowledge of the genetic determinants of susceptibility to tinnitus remains limited. Results We performed a two-stage genome-wide association study (GWAS) and identified that two single nucleotide polymorphisms (SNPs), rs2846071 located in the intergenic region at 11q13.5 (odds ratio [OR] = 2.14, 95% confidence interval [CI] = 1.96–3.40, combined P = 4.89 × 10− 6) and rs4149577 located in the intron of TNFRSF1A gene at 12p13.31 (OR = 2.05, 95% CI = 1.89–2.51, combined P = 6.88 × 10− 6), are significantly associated with the susceptibility to noise-induced tinnitus. Furthermore, the expression quantitative trait loci (eQTL) analyses revealed that rs2846071 is significantly correlated with the expression of WNT11 gene, and rs4149577 with the expression of TNFRSF1A gene in multiple brain tissues (all P < 0.05). The newly identified candidate gene WNT11 is involved in Wnt pathway, and TNFRSF1A in the tumor necrosis factor pathway, respectively. Pathway enrichment analyses also showed that these two pathways are closely relevant to tinnitus. Conclusions Our findings highlight two novel loci at 11q13.5 and 12p13.31 conferring susceptibility to noise-induced tinnitus. and suggest that the WNT11 and TNFRSF1A genes might be the candidate causal targets of 11q13.5 and 12p13.31 loci, respectively.

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Genome-wide Association Study for Noise-induced Cochlear Synaptopathy

10.1101/311407 ◽

2018 ◽

Keyword(s):

Association Study ◽

Candidate Genes ◽

Noise Exposure ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Positional Candidate ◽

Genome Wide ◽

Hybrid Mouse Diversity Panel ◽

Susceptibility To Noise ◽

Cell Synapse

Article SummaryIn order to elucidate the genetic architecture of the auditory hair cell synapse and the susceptibility to noise-induced cochlear synaptopathy, we are providing the first genome-wide association study with 111 strains (n=695) of the Hybrid Mouse Diversity Panel based upon the strain variation of the wave 1 P1-N1 amplitude of the auditory brainstem responses both before and after noise exposure. Based on this association analysis and our cochlear gene expression data, we identified several novel loci and prioritized positional candidate genes related to cochlear synaptopathy, especially after exposure to noise.AbstractThis is the first genome-wide association study (GWAS) with the Hybrid Mouse Diversity Panel (HMDP) to define the genetic landscape of the auditory hair cell synapse and the susceptibility to noise-induced cochlear synaptopathy. We tested 5-week old female mice (n=695) from 111 HMDP strains (n= 6-7/strain) at baseline and post noise exposure using ABR wave 1 suprathreshold amplitudes (P1-N1 at 80 dB SPL) at 8, 12, 16, 24 and 32 kHz tone burst stimuli. Mice were exposed for 2 hours to 10 kHz octave band noise (OBN) at 108 dB SPL. A broad range of suprathreshold ABR wave 1 amplitude were detected across the HMDP strains. At the genome-wide significance threshold (-logP = 5.39), associations on Chr. 3 and Chr. 16 were identified at baseline. Also, association peaks on Chr. 2 and Chr. 13 were determined post noise exposure. In order to prioritize candidate genes, we generated gene expression microarray profiles using RNA isolated from cochleae in 64 HMDP strains (n =3 arrays per strain). We then used EMMA to perform an association analysis between all SNPs and array probes mapping within each region. A total of 17 genes (2 within Chr. 3 association, 6 within Chr. 2 association and 9 within Chr. 13 association) of these 3 loci were identified with at least 1 probe whose expression was regulated by a significant cis eQTL in the cochlea. Also, the genetic architecture of noise induced cochlear synaptopathy is distinct from that of baseline auditory nerve/synapse integrity. In summary, from this GWAS and our eQTL data, we identified 4 novel loci and prioritized positional candidate genes related to cochlear synaptopathy at baseline and after exposure to noise.

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