A Large Genome-Wide Association Study of Age-Related Hearing Impairment Using Electronic Health Records

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. © 2016 hoffmann et al.