eQTL Analysis in Humans
eQTL Analysis in Humans
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DOI：
10.1007/978-1-60761-247-6_17
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发表时间：
2009-01-01
期刊：
影响因子：
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通讯作者：
Jansen, Ritsert C.
中科院分区：
文献类型：
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作者：
Franke, Lude;Jansen, Ritsert C.
改善人类健康是医学研究的一个主要目标，但这需要考虑到个人之间的差异，因为每个人都携带不同的基因变异组合，并面临不同的环境条件，这可能导致对疾病的易感性存在差异。随着20世纪80年代分子标记的出现，对个体进行基因分型成为可能（即，在数百个基因组位置中检测本地DNA序列变体的存在或缺失）。通过使用系谱数据，这种DNA序列变异可以与疾病易感性相关。事实证明，这种关联分析很难用于更复杂的疾病。最近，随着基因分型成本的降低，对大量不相关个体的自然种群进行分析成为可能，并导致许多基因（以及这些基因中的遗传变异）与复杂疾病的关联。不幸的是，对于这些基因和它们的蛋白质中的相当一部分，我们还不清楚它们的下游影响是什么。研究这些基因和蛋白质的表达有助于揭示这些变异对这些和其他基因、蛋白质、代谢物和表型的表达的影响。在本章中，我们将重点介绍在一个自然种群中对基因表达的高通量和全基因组测量，以及随后使用带有数十万个单核苷酸多态性（SNP）标记的寡核苷酸阵列将表达变异与DNA上的“表达数量性状位点”（eqtl）联系起来，这些标记可以很好地捕获大多数人类遗传变异。这一策略已成功应用于多种疾病，如乳糜泻（Hunt et al. 2008, Nat Genet 40,395 -402）和哮喘（Moffatt et al. 2007, natzzre448,470 -473）：已确定影响顺式或反式基因表达水平的相关遗传变异，为了解受这些疾病影响的生物学途径提供了见解。
Improving human health is a major aim of medical research, but it requires that variation between individuals be taken into account since each person carries a different combination of gene variants and is exposed to different environmental conditions, which can cause differences in susceptibility to diseases. With the advent of molecular markers in the 1980s, it became possible to genotype individuals (i.e., to detect the presence or absence of local DNA sequence variants at each of hundreds of genome positions). This DNA sequence variation could then be related to disease susceptibility by using pedigree data. Such linkage analyses proved to be difficult for more complex diseases. Recently, with the decreasing costs of genotyping, analyses of large natural populations of unrelated individuals became possible and resulted in the association of many genes (and genetic variants in these genes) with complex diseases. Unfortunately, for a considerable proportion of these genes and their proteins, it is not vet clear what their downstream effects are. Studying the expression of these genes and proteins can help to uncover the effects of these variants on the expression of these and other genes, proteins, metabolites, and phenotypes. In this chapter, we focus on the high-throughput and genome-wide measurement of gene expression in a natural population of unrelated humans, and on the subsequent association of variation in expression to "expression quantitative trait loci" (eQTLs) on DNA using oligonucleotide arrays with hundreds of thousands of single-nucleotide polymorphism (SNP) markers that capture most of the human genetic variation well. This strategy has been successfully applied to several diseases such as celiac disease (Hunt et al. 2008, Nat Genet 40, 395-402) and asthma (Moffatt et al. 2007, Natzzre448, 470-473): associated genetic variants have been identified that affect levels of gene expression in cis or in trans, providing insight into the biological pathways affected by these diseases.