A genome-wide association study for age-related hearing impairment in the Saami
A genome-wide association study for age-related hearing impairment in the Saami
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DOI：
10.1038/ejhg.2009.234
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发表时间：
2010-06-01
影响因子：
5.2
通讯作者：
Van Camp, Guy
中科院分区：
文献类型：
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作者：
Van Laer, Lut;Huyghe, Jeroen R.;Van Camp, Guy
本研究旨在帮助阐明年龄相关性听力障碍（ARHI）的遗传基础，这是一种常见的多因素疾病，遗传性研究证明其具有重要的遗传贡献。我们在芬兰萨米人中进行了一项全基因组关联研究 (GWAS)，这是一个小型、古老、基因隔离的种群，没有人口扩张的证据。选择该研究群体的动机是其预期的较高 LD 程度，可能为关联映射提供巨大的功效优势。 DNA 样本和听力测量数据采集自 352 名年龄在 50 至 75 岁之间的芬兰萨米人。为了减轻多重测试的负担，我们将主成分（PC）分析应用于多元听力表型。前三台 PC 捕获了 80% 的听力阈值变化，同时保持了生物学上重要的听力特征。所有受试者均使用 Affymetrix 100 K 芯片进行基因分型。为了考虑受试者之间的多个相关性水平以及群体分层，使用混合模型进行关联测试。我们总结了所研究的三个性状的顶级关联信号。排名最高的 SNP rs457717（P 值 3.55x10(-7)）与 PC3 相关，位于包含 IQ 基序的 GTP 酶激活样蛋白 (IQGAP2) 的内含子中。有趣的是，PC1 中排名第七的 SNP rs161927（P 值 0.000149）位于代谢型谷氨酸受体 7 基因 (GRM7) 的紧下游。由于先前对欧洲和芬兰样本集的 GWAS 已经表明 GRM7 在 ARHI 中发挥作用，因此这项研究为该基因的参与提供了进一步的证据。欧洲人类遗传学杂志 (2010) 18, 685-693; doi：10.1038/ejhg.2009.234； 2010 年 1 月 13 日在线发布
This study aimed at contributing to the elucidation of the genetic basis of age-related hearing impairment (ARHI), a common multifactorial disease with an important genetic contribution as demonstrated by heritability studies. We conducted a genome-wide association study (GWAS) in the Finnish Saami, a small, ancient, genetically isolated population without evidence of demographic expansion. The choice of this study population was motivated by its anticipated higher extent of LD, potentially offering a substantial power advantage for association mapping. DNA samples and audiometric measurements were collected from 352 Finnish Saami individuals, aged between 50 and 75 years. To reduce the burden of multiple testing, we applied principal component (PC) analysis to the multivariate audiometric phenotype. The first three PCs captured 80% of the variation in hearing thresholds, while maintaining biologically important audiometric features. All subjects were genotyped with the Affymetrix 100 K chip. To account for multiple levels of relatedness among subjects, as well as for population stratification, association testing was performed using a mixed model. We summarised the top-ranking association signals for the three traits under study. The top-ranked SNP, rs457717 (P-value 3.55x10(-7)), was associated with PC3 and was localised in an intron of the IQ motif-containing GTPase-activating-like protein (IQGAP2). Intriguingly, the SNP rs161927 (P-value 0.000149), seventh-ranked for PC1, was positioned immediately downstream from the metabotropic glutamate receptor-7 gene (GRM7). As a previous GWAS of a European and Finnish sample set already suggested a role for GRM7 in ARHI, this study provides further evidence for the involvement of this gene. European Journal of Human Genetics (2010) 18, 685-693; doi: 10.1038/ejhg.2009.234; published online 13 January 2010