GRM7 variants confer susceptibility to age-related hearing impairment
GRM7 variants confer susceptibility to age-related hearing impairment
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DOI：
10.1093/hmg/ddn402
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发表时间：
2009-02-15
影响因子：
3.5
通讯作者：
Van Camp, Guy
中科院分区：
文献类型：
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作者：
Friedman, Rick A.;Van Laer, Lut;Van Camp, Guy
年龄相关性听力障碍（ARHI），或老年性耳聋，是老年人最普遍的感觉障碍。ARHI是一种由环境和遗传因素相互作用引起的复杂疾病。在这里，我们描述了ARHI的第一个全基因组关联研究的结果。这项研究从6个欧洲国家的8个中心收集的3434个人中选择了846例病例和846例对照。分别在Affymetrix 500K基因芯片(R)上对每个中心的病例和对照组DNA池进行等位型分析。利用个体基因分型方法，对来自非芬兰欧洲样本组（1332个样本）的252个排名靠前的单核苷酸多态性（snp）和来自芬兰样本组（360个样本）的177个排名靠前的snp进行了确认。随后，23个最有趣的snp在一个独立的欧洲复制组（138个样本）中进行了单独的基因分型。这导致鉴定出位于GRM7的高度显著且可复制的SNP， GRM7是编码代谢型谷氨酸受体7的基因。同样在芬兰样本组中，两个GRM7 snp是显著的，尽管在基因的不同区域。芬兰人在基因上与其他欧洲人不同，这可能是由于等位基因的异质性。我们对人和小鼠进行了组织化学研究，发现mGluR7在内耳毛细胞和螺旋神经节细胞中表达。综上所述，这些数据表明，GRM7的共同等位基因可能通过改变对谷氨酸兴奋毒性的易感性的机制，增加了个体发生ARHI的风险。
Age-related hearing impairment (ARHI), or presbycusis, is the most prevalent sensory impairment in the elderly. ARHI is a complex disease caused by an interaction between environmental and genetic factors. Here we describe the results of the first whole genome association study for ARHI. The study was performed using 846 cases and 846 controls selected from 3434 individuals collected by eight centers in six European countries. DNA pools for cases and controls were allelotyped on the Affymetrix 500K GeneChip (R) for each center separately. The 252 top-ranked single nucleotide polymorphisms (SNPs) identified in a non-Finnish European sample group (1332 samples) and the 177 top-ranked SNPs from a Finnish sample group (360 samples) were confirmed using individual genotyping. Subsequently, the 23 most interesting SNPs were individually genotyped in an independent European replication group (138 samples). This resulted in the identification of a highly significant and replicated SNP located in GRM7, the gene encoding metabotropic glutamate receptor type 7. Also in the Finnish sample group, two GRM7 SNPs were significant, albeit in a different region of the gene. As the Finnish are genetically distinct from the rest of the European population, this may be due to allelic heterogeneity. We performed histochemical studies in human and mouse and showed that mGluR7 is expressed in hair cells and in spiral ganglion cells of the inner ear. Together these data indicate that common alleles of GRM7 contribute to an individual's risk of developing ARHI, possibly through a mechanism of altered susceptibility to glutamate excitotoxicity.