title: The Genetic Architecture of Noise-Induced Hearing Loss: Evidence for a Gene-by-Environment Interaction.
abstract: The discovery of environmentally specific genetic effects is crucial to the understanding of complex traits, such as susceptibility to noise-induced hearing loss (NIHL). We describe the first genome-wide association study (GWAS) for NIHL in a large and well-characterized population of inbred mouse strains, known as the Hybrid Mouse Diversity Panel (HMDP). We recorded auditory brainstem response (ABR) thresholds both pre and post 2-hr exposure to 10-kHz octave band noise at 108 dB sound pressure level in 5-6-wk-old female mice from the HMDP (4-5 mice/strain). From the observation that NIHL susceptibility varied among the strains, we performed a GWAS with correction for population structure and mapped a locus on chromosome 6 that was statistically significantly associated with two adjacent frequencies. We then used a "genetical genomics" approach that included the analysis of cochlear eQTLs to identify candidate genes within the GWAS QTL. In order to validate the gene-by-environment interaction, we compared the effects of the postnoise exposure locus with that from the same unexposed strains. The most significant SNP at chromosome 6 (rs37517079) was associated with noise susceptibility, but was not significant at the same frequencies in our unexposed study. These findings demonstrate that the genetic architecture of NIHL is distinct from that of unexposed hearing levels and provide strong evidence for gene-by-environment interactions in NIHL.
authors: Tina and Rick Caruso Department of Otolaryngology, Zilkha Neurogenetic Institute Graduate Program in Surgical Sciences, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
authors: Joel
authors: 0000-0002-0377-5704
authors: J
authors: Lavinsky
authors: Tina and Rick Caruso Department of Otolaryngology, Zilkha Neurogenetic Institute.
authors: Marshall
authors: M
authors: Ge
authors: Department of Preventive Medicine and Institute for Genetic Medicine, USC Keck School of Medicine, University of Southern California, Los Angeles, California 90033.
authors: Amanda L
authors: 0000-0002-1013-8789
authors: AL
authors: Crow
authors: Department of Human Genetics.
authors: Calvin
authors: 0000-0002-3723-6688
authors: C
authors: Pan
authors: Tina and Rick Caruso Department of Otolaryngology, Zilkha Neurogenetic Institute.
authors: Juemei
authors: 0000-0002-5344-2510
authors: J
authors: Wang
authors: Tina and Rick Caruso Department of Otolaryngology, Zilkha Neurogenetic Institute.
authors: Pezhman
authors: P
authors: Salehi
authors: Tina and Rick Caruso Department of Otolaryngology, Zilkha Neurogenetic Institute.
authors: Anthony
authors: 0000-0002-9790-1942
authors: A
authors: Myint
authors: Department of Computer Science.
authors: Eleazar
authors: 0000-0003-1149-4758
authors: E
authors: Eskin
authors: Department of Preventive Medicine and Institute for Genetic Medicine, USC Keck School of Medicine, University of Southern California, Los Angeles, California 90033.
authors: Hooman
authors: H
authors: Allayee
authors: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, California 90024.
authors: Aldons J
authors: 0000-0001-9013-0228
authors: AJ
authors: Lusis
authors: Tina and Rick Caruso Department of Otolaryngology, Zilkha Neurogenetic Institute rick.friedman@med.usc.edu.
authors: Rick A
authors: 0000-0002-5490-8562
authors: RA
authors: Friedman
mesh_terms: D000818:Animals; D016000:Cluster Analysis; D003051:Cochlea; D004195:Disease Models, Animal; D004777:Environment; D005260:Female; D020869:Gene Expression Profiling; D059647:Gene-Environment Interaction; D000068617:Genetic Background; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006317:Hearing Loss, Noise-Induced / Q000175:diagnosis / Q000209:etiology*; D006320:Hearing Tests; D051379:Mice; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D059467:Transcriptome
keywords: GWAS; HMDP; NIHL; eQTL; gene-by-environment