一项利用电子健康记录进行的与年龄相关听力损失的大型全基因组关联研究。
A Large Genome-Wide Association Study of Age-Related Hearing Impairment Using Electronic Health Records.
作者信息
Hoffmann Thomas J, Keats Bronya J, Yoshikawa Noriko, Schaefer Catherine, Risch Neil, Lustig Lawrence R
机构信息
Department of Epidemiology and Biostatistics, and Institute for Human Genetics, University of California San Francisco, San Francisco, United States of America.
Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, United States of America.
出版信息
PLoS Genet. 2016 Oct 20;12(10):e1006371. doi: 10.1371/journal.pgen.1006371. eCollection 2016 Oct.
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.
年龄相关性听力减退（ARHI）是最常见的感觉障碍之一，虽可缓解，但无法治愈或消除。为确定ARHI潜在的遗传影响因素，我们在“成人健康与衰老遗传流行病学研究”（GERA）队列中的6527例非西班牙裔白人病例和45882例对照中开展了一项ARHI的全基因组关联研究。我们鉴定出两个新的全基因组显著单核苷酸多态性（SNP）：rs4932196（优势比 = 1.185，p = 4.0×10⁻¹¹），位于ISG20基因下游3'方向52Kb处，该结果在对GERA其他种族/族裔群体的荟萃分析（1025例病例，12388例对照，p = 0.00094）以及英国生物银行病例对照分析（30802例自我报告病例，78586例对照，p = 0.015）中得到重复验证；还有rs58389158（优势比 = 1.132，p = 1.8×10⁻⁹），在英国生物银行中得到重复验证（p = 0.00021）。后一个SNP位于第8外显子外侧，与TRIOBP基因第7外显子中的错义SNP rs5756795高度相关（r² = 0.96），TRIOBP基因先前与语前非综合征性听力损失相关。我们进一步在GERA部分人群（4903人）可获取的听力学家记录的表型中对这些SNP进行检测，根据病例/对照状态分层，构建独立重复检验，发现rs58389158对言语接受阈值（SRT；GERA总体荟萃分析p = 1.9×10⁻⁶）有显著影响。我们还对其他132个先前鉴定的听力损失基因的外显子内变体进行检测，鉴定出另外两个常见的显著SNP：rs2877561（ILDR1中的同义突变，p = 6.2×10⁻⁵），在英国生物银行中得到重复验证（p = 0.00057），且在GERA中对SRT（p = 0.00019）和言语辨别得分（SDS；p = 0.0019）有显著影响；以及rs9493627（EYA4中的错义突变，p = 0.00011），在英国生物银行（p = 0.0095）、GERA其他群体（p = 0.0080）中得到重复验证，且对SRT有一致的显著结果（p = 0.041），对SDS有提示性结果（p = 0.081）。拥有全基因组关联研究数据和电子健康记录的大型队列可能是描绘ARHI遗传结构的一种有用方法。
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