The Genetic Architecture of Hearing Impairment in Mice: Evidence for Frequency-Specific Genetic Determinants.
Genome-wide association studies (GWAS) have been successfully applied in humans for the study of many complex phenotypes. However, identification of the genetic determinants of hearing in adults has been hampered, in part, by the relative inability to control for environmental factors that might affect hearing throughout the lifetime, as well as a large degree of phenotypic heterogeneity. These and other factors have limited the number of large-scale studies performed in humans that have identified candidate genes that contribute to the etiology of this complex trait. To address these limitations, we performed a GWAS analysis using a set of inbred mouse strains from the Hybrid Mouse Diversity Panel. Among 99 strains characterized, we observed approximately two-fold to five-fold variation in hearing at six different frequencies, which are differentiated biologically from each other by the location in the cochlea where each frequency is registered. Among all frequencies tested, we identified a total of nine significant loci, several of which contained promising candidate genes for follow-up study. Taken together, our results indicate the existence of both genes that affect global cochlear function, as well as anatomical- and frequency-specific genes, and further demonstrate the complex nature of mammalian hearing variation.
Department of Preventive Medicine and Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90033.
Amanda L
AL
Crow
House Ear Institute, Los Angeles, California 90057.
Jeffrey
J
Ohmen
Department of Otolaryngology and Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California 90033.
Juemei
J
Wang
Department of Otolaryngology and Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California 90033.
Joel
J
Lavinsky
Department of Preventive Medicine and Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90033.
Jaana
J
Hartiala
Department of Otolaryngology, Head and Neck Surgery, Eye & ENT Hospital of Fudan University, Shanghai 200031, China.
Qingzhong
Q
Li
Clinical Laboratory Department, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province 330006, China.
Xin
X
Li
Department of Otolaryngology and Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California 90033.
Pezhman
P
Salehide
Department of Computer Science and Inter-Departmental Program in Bioinformatics, University of California, Los Angeles, California 90095.
Eleazar
E
Eskin
Departments of Human Genetics, Medicine, and Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California 90095.
Calvin
C
Pan
Departments of Human Genetics, Medicine, and Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California 90095.
Aldons J
AJ
Lusis
Department of Preventive Medicine and Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90033.
Hooman
H
Allayee
Department of Otolaryngology and Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California 90033 rick.friedman@med.usc.edu.
Rick A
RA
Friedman
D000818:Animals; D001309:Auditory Threshold; D005260:Female; D016678:Genome; D055106:Genome-Wide Association Study; D034381:Hearing Loss / Q000235:genetics*; D051379:Mice; D008815:Mice, Inbred Strains; D040641:Quantitative Trait Loci
ABR; Hybrid Mouse Diversity Panel (HMDP); cochlear function; genetics; genome-wide association study (GWAS); genomics; hearing