Joel Lavinsky1, Guilherme Kasperbauer1, Ricardo F Bento2, Aline Mendonça1, Juemei Wang3, Amanda L Crow3, Hooman Allayee3, Rick A Friedman4. 1. Postgraduate Program in Medicine: Surgical Sciences, Federal University of Rio Grande do Sul, Porto Alegre, Brazil. 2. Department of Otolaryngology, University of São Paulo, La Jolla, California, USA. 3. Keck School of Medicine of USC, Los Angeles, California, USA. 4. University of California, San Diego, California, USA.
Abstract
BACKGROUND: Although several candidate-gene association studies have been conducted to investigate noise-induced hearing loss (NIHL) in humans, most are underpowered, unreplicated, and account for only a fraction of the genetic risk. Mouse genome-wide association studies (GWASs) have revolutionized the field of genetics and have led to the discovery of hundreds of genes involved in complex traits. The hybrid mouse diversity panel (HMDP) is a collection of classic inbred and recombinant inbred strains whose genomes have been either genotyped at high resolution or sequenced. To further investigate the genetics of NIHL, we report the first GWAS based on distortion product otoacoustic emission (DPOAE) measurements and the HMDP. METHODS: A total of 102 strains (n = 635) from the HMDP were evaluated based on DPOAE suprathreshold amplitudes before and after noise exposure. DPOAE amplitude variation was set at 60 and 70 dB SPL of the primary tones for each frequency separately (8, 11.3, 16, 22.6, and 32 kHz). These values provided an indirect assessment of outer hair cell integrity. Six-week-old mice were exposed for 2 h to 10 kHz octave-band noise at 108 dB SPL. To perform local expression quantitative trait locus (eQTL) analysis, gene expression microarray profiles were generated using cochlear RNA from 64 hybrid mouse strains (n = 3 arrays per strain). RESULTS: Several new loci were identified and positional candidate-genes associated with NIHL were prioritized, especially after noise exposure (1 locus at baseline and 5 loci after exposure). A total of 35 candidate genes in these 6 loci were identified with at least 1 probe whose expression was regulated by a significant cis-eQTL in the cochlea. After careful analysis of the candidate genes based on cochlear gene expression, 2 candidate genes were prioritized: Eya1 (baseline) and Efr3a (post-exposure). DISCUSSION AND CONCLUSION: For the first time, an association analysis with correction for population structure was used to map several loci for hearing traits in inbred strains of mice based on DPOAE suprathreshold amplitudes before and after noise exposure. Our results identified a number of novel loci and candidate genes for susceptibility to NIHL, especially the Eya1 and Efr3a genes. Our findings validate the power of the HMDP for detecting NIHL susceptibility genes.
BACKGROUND: Although several candidate-gene association studies have been conducted to investigate noise-induced hearing loss (NIHL) in humans, most are underpowered, unreplicated, and account for only a fraction of the genetic risk. Mouse genome-wide association studies (GWASs) have revolutionized the field of genetics and have led to the discovery of hundreds of genes involved in complex traits. The hybrid mouse diversity panel (HMDP) is a collection of classic inbred and recombinant inbred strains whose genomes have been either genotyped at high resolution or sequenced. To further investigate the genetics of NIHL, we report the first GWAS based on distortion product otoacoustic emission (DPOAE) measurements and the HMDP. METHODS: A total of 102 strains (n = 635) from the HMDP were evaluated based on DPOAE suprathreshold amplitudes before and after noise exposure. DPOAE amplitude variation was set at 60 and 70 dB SPL of the primary tones for each frequency separately (8, 11.3, 16, 22.6, and 32 kHz). These values provided an indirect assessment of outer hair cell integrity. Six-week-old mice were exposed for 2 h to 10 kHz octave-band noise at 108 dB SPL. To perform local expression quantitative trait locus (eQTL) analysis, gene expression microarray profiles were generated using cochlear RNA from 64 hybrid mouse strains (n = 3 arrays per strain). RESULTS: Several new loci were identified and positional candidate-genes associated with NIHL were prioritized, especially after noise exposure (1 locus at baseline and 5 loci after exposure). A total of 35 candidate genes in these 6 loci were identified with at least 1 probe whose expression was regulated by a significant cis-eQTL in the cochlea. After careful analysis of the candidate genes based on cochlear gene expression, 2 candidate genes were prioritized: Eya1 (baseline) and Efr3a (post-exposure). DISCUSSION AND CONCLUSION: For the first time, an association analysis with correction for population structure was used to map several loci for hearing traits in inbred strains of mice based on DPOAE suprathreshold amplitudes before and after noise exposure. Our results identified a number of novel loci and candidate genes for susceptibility to NIHL, especially the Eya1 and Efr3a genes. Our findings validate the power of the HMDP for detecting NIHL susceptibility genes.
Authors: Marja Heinonen-Guzejev; Heikki S Vuorinen; Helena Mussalo-Rauhamaa; Kauko Heikkilä; Markku Koskenvuo; Jaakko Kaprio Journal: Arch Environ Health Date: 2004-08
Authors: K K Ohlemiller; S L McFadden; D L Ding; D G Flood; A G Reaume; E K Hoffman; R W Scott; J S Wright; G V Putcha; R J Salvi Journal: Audiol Neurootol Date: 1999 Sep-Oct Impact factor: 1.854
Authors: Charles R Farber; Brian J Bennett; Luz Orozco; Wei Zou; Ana Lira; Emrah Kostem; Hyun Min Kang; Nicholas Furlotte; Ani Berberyan; Anatole Ghazalpour; Jaijam Suwanwela; Thomas A Drake; Eleazar Eskin; Q Tian Wang; Steven L Teitelbaum; Aldons J Lusis Journal: PLoS Genet Date: 2011-04-07 Impact factor: 5.917