title: A Large Genome-Wide Association Study of Age-Related Hearing Impairment Using Electronic Health Records.
abstract: Age-related hearing impairment (ARHI), one of the most common sensory disorders, can be mitigated, but not cured or eliminated. To identify genetic influences underlying ARHI, we conducted a genome-wide association study of ARHI in 6,527 cases and 45,882 controls among the non-Hispanic whites from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. We identified two novel genome-wide significant SNPs: rs4932196 (odds ratio = 1.185, p = 4.0x10-11), 52Kb 3' of ISG20, which replicated in a meta-analysis of the other GERA race/ethnicity groups (1,025 cases, 12,388 controls, p = 0.00094) and in a UK Biobank case-control analysis (30,802 self-reported cases, 78,586 controls, p = 0.015); and rs58389158 (odds ratio = 1.132, p = 1.8x10-9), which replicated in the UK Biobank (p = 0.00021). The latter SNP lies just outside exon 8 and is highly correlated (r2 = 0.96) with the missense SNP rs5756795 in exon 7 of TRIOBP, a gene previously associated with prelingual nonsyndromic hearing loss. We further tested these SNPs in phenotypes from audiologist notes available on a subset of GERA (4,903 individuals), stratified by case/control status, to construct an independent replication test, and found a significant effect of rs58389158 on speech reception threshold (SRT; overall GERA meta-analysis p = 1.9x10-6). We also tested variants within exons of 132 other previously-identified hearing loss genes, and identified two common additional significant SNPs: rs2877561 (synonymous change in ILDR1, p = 6.2x10-5), which replicated in the UK Biobank (p = 0.00057), and had a significant GERA SRT (p = 0.00019) and speech discrimination score (SDS; p = 0.0019); and rs9493627 (missense change in EYA4, p = 0.00011) which replicated in the UK Biobank (p = 0.0095), other GERA groups (p = 0.0080), and had a consistent significant result for SRT (p = 0.041) and suggestive result for SDS (p = 0.081). Large cohorts with GWAS data and electronic health records may be a useful method to characterize the genetic architecture of ARHI.
authors.affiliation: Department of Epidemiology and Biostatistics, and Institute for Human Genetics, University of California San Francisco, San Francisco, United States of America.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hoffmann
authors.affiliation: Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, United States of America.
authors.forename: Bronya J
authors.initials: BJ
authors.lastname: Keats
authors.affiliation: Department of Head and Neck Surgery, Kaiser Permanente Medical Center, Oakland, United States of America.
authors.forename: Noriko
authors.initials: N
authors.lastname: Yoshikawa
authors.affiliation: Kaiser Permanente Northern California Division of Research, Oakland, United States of America.
authors.forename: Catherine
authors.identifier: http://orcid.org/0000-0003-2644-055X
authors.initials: C
authors.lastname: Schaefer
authors.affiliation: Department of Epidemiology and Biostatistics, and Institute for Human Genetics, University of California San Francisco, San Francisco, United States of America.|Kaiser Permanente Northern California Division of Research, Oakland, United States of America.
authors.forename: Neil
authors.initials: N
authors.lastname: Risch
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Columbia University Medical Center, Columbia, United States of America.|New York Presbyterian Hospital, New York, United States of America.
authors.forename: Lawrence R
authors.identifier: http://orcid.org/0000-0001-6718-9838
authors.initials: LR
authors.lastname: Lustig
mesh_terms: D000328:Adult; D000375:Aging / Q000235:genetics / Q000473:pathology; D057286:Electronic Health Records; D005006:Ethnicity; D005092:Exonucleases / Q000235:genetics*; D005095:Exoribonucleases; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D034381:Hearing Loss / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011304:Presbycusis / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D011956:Receptors, Cell Surface / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics*
chemical_list: C117736:EYA4 protein, human; C493788:ILDR1 protein, human; D008840:Microfilament Proteins; D011956:Receptors, Cell Surface; C425471:TRIOBP protein, human; D015534:Trans-Activators; D005092:Exonucleases; D005095:Exoribonucleases; C112346:ISG20 protein, human