淋巴细胞计数全基因组关联研究联合基因表达数据分析揭示新的哮喘候选基因
2012/02/29
近期完成的全基因组关联研究（GWAS）已发现了一些与复杂人体疾病有关的新型遗传关联性。尽管获得了这些结果，来自GWAS 的结果仅解释了疾病遗传性的一小部分，即遗传性丢失问题。目前，对遗传性丢失的可能原因进行了研究，包括小个体效应规模的常见变异体，但采用标准的GWAS方法并不一定能发现这些问题。本研究旨在探索一种补充方法，与GWAS研究的功能性数据联合，鉴别新的小效应规模的遗传相关性。为此，我们对462名哈特莱特人的淋巴细胞计数进行GWAS研究，而淋巴细胞计数是与哮喘相关的生理性定量特征。同时，我们采用全基因组表达研究对96个哈特莱特人的淋巴母细胞系（LCLs）进行分析。不同个体间表达水平与淋巴细胞计数最为相关的193个基因附近的变异体的GWAS数据支持支持遗传相关性。有趣的是，这些变异体存在富集，且与哮喘易感性相关，而且该结果具有可重复性。相关的位点包括前期发现的与哮喘易感性相关的基因、新的候选基因，后者与T细胞受体信号和ATP合成有关。因此，我们的研究结果找到了新的哮喘易感性候选基因。此外，我们的结果也支持许多小效应位点也能够影响淋巴细胞计数和哮喘易感性。
（陈欣 审校）
Hum Mol Genet. 2012 Jan 27. [Epub ahead of print]
Source
Department of Human Genetics, and.
Department of Human Genetics, and.
Abstract
Recent genome-wide association studies (GWAS) have identified a number of novel genetic associations with complex human diseases. In spite of these successes, results from GWAS generally explain only a small proportion of disease heritability, an observation termed the "missing heritability problem." Several sources for the missing heritability have been proposed, including the contribution of many common variants with small individual effect sizes, which cannot be reliably found using the standard GWAS approach. The goal of our study was to explore a complimentary approach, which combines GWAS results with functional data in order to identify novel genetic associations with small effect sizes. To do so, we conducted a GWAS for lymphocyte count, a physiologic quantitative trait associated with asthma, in 462 Hutterites. In parallel, we performed a genome-wide gene expression study in lymphoblastoid cell lines (LCLs) from 96 Hutterites. We found significant support for genetic associations using the GWAS data when we considered variants near the 193 genes whose expression levels across individuals were most correlated with lymphocyte counts. Interestingly, these variants are also enriched with signatures of an association with asthma susceptibility, an observation we were able to replicate. The associated loci include genes previously implicated in asthma susceptibility as well as novel candidate genes enriched for functions related to T cell receptor signaling and ATP synthesis. Our results, therefore, establish a new set of asthma susceptibility candidate genes. More generally, our observations support the notion that many loci of small effects influence variation in lymphocyte count and asthma susceptibility.
Recent genome-wide association studies (GWAS) have identified a number of novel genetic associations with complex human diseases. In spite of these successes, results from GWAS generally explain only a small proportion of disease heritability, an observation termed the "missing heritability problem." Several sources for the missing heritability have been proposed, including the contribution of many common variants with small individual effect sizes, which cannot be reliably found using the standard GWAS approach. The goal of our study was to explore a complimentary approach, which combines GWAS results with functional data in order to identify novel genetic associations with small effect sizes. To do so, we conducted a GWAS for lymphocyte count, a physiologic quantitative trait associated with asthma, in 462 Hutterites. In parallel, we performed a genome-wide gene expression study in lymphoblastoid cell lines (LCLs) from 96 Hutterites. We found significant support for genetic associations using the GWAS data when we considered variants near the 193 genes whose expression levels across individuals were most correlated with lymphocyte counts. Interestingly, these variants are also enriched with signatures of an association with asthma susceptibility, an observation we were able to replicate. The associated loci include genes previously implicated in asthma susceptibility as well as novel candidate genes enriched for functions related to T cell receptor signaling and ATP synthesis. Our results, therefore, establish a new set of asthma susceptibility candidate genes. More generally, our observations support the notion that many loci of small effects influence variation in lymphocyte count and asthma susceptibility.
Hum Mol Genet. 2012 Jan 27. [Epub ahead of print]
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