For Personal Use. Only Reproduce with Permission from the Lancet Publishing Group. Population Stratification and Spurious Allelic Association
For Personal Use. Only Reproduce with Permission from the Lancet Publishing Group. Population Stratification and Spurious Allelic Association
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通讯作者：
L. Cardon;L. Palmer;L. Cardon;L. Palmer
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作者：
L. Cardon;L. Palmer;L. Cardon;L. Palmer
过去二十年来，发达国家许多复杂的人类疾病，如哮喘、心血管疾病和糖尿病的患病率大幅上升。同一时期，此类疾病的遗传原因越来越受到重视，作为更好地了解其发病机制的一种手段，最终目标是改进预防策略、诊断工具和治疗。 3-8 正在花费大量精力尝试检测导致复杂疾病的遗传位点。 9 关联和连锁研究包括两种主要策略：关联研究的目的是在人群水平上寻找易患疾病的等位基因；连锁研究的重点是家庭隔离。尽管这两种策略都具有令人信服的优势，但关联分析的应用范围更广，并且在未来可能会进一步传播，尤其是在药物遗传学领域。 5 分子遗传学的技术发展以及源自人类基因组测序项目的基因特异性变体的使用促进了这些研究。 10 此外，人类基因组中匿名 DNA 序列变体的广泛目录正在编制中。 11,12 一些大规模、基于人群的人类样本已经或预计将被收集（例如，DNA 变体在药物开发中的使用正在扩大。4 高通量分子技术、许多遗传变体和基于人群的样本的结合为了解常见疾病的病因提供了独特的机会。遗传变体（或多态性）源自新的突变。最简单的多态性类型是 单碱基突变，将一个核苷酸替换为另一个核苷酸，称为单核苷酸多态性 (SNP)。 SNP 不一定与疾病或结果有任何相关性；它们可以是基因内或基因之间的匿名变异（即，在蛋白质编码或基因功能方面未表征），也可以是功能性、因果性突变。人们认为人类基因组中存在的单核苷酸多态性（SNP）比任何其他类型都多 的多态性。 20 已报告近 300 万种变异，并在公共数据库中进行编目。在这篇综述中，我们将注意力限制在 SNP 上，因为它们广泛存在和使用，但所描述的问题和原则是一般性的，适用于其他 DNA 多态性。遗传关联研究旨在将群体之间疾病频率的差异（或连续变化性状的性状水平）与等位基因频率的差异相关联 在 SNP 处。因此，SNP 的两种变异形式（等位基因）的频率对于鉴定影响疾病的基因至关重要。用于评估基因型-表型相关性的最简单的研究设计......
Prevalence of many complex human diseases such as asthma, cardiovascular disease, and diabetes has risen greatly over the past two decades in developed countries. During the same period, the genetic causes of such diseases have been increasingly emphasised as a means to better understand their pathogenesis, with the ultimate goal of improvement of preventive strategies, diagnostic tools, and treatment. 3–8 Considerable effort is being expended in attempts to detect genetic loci contributing to complex diseases. 9 Association and linkage studies comprise the two dominant strategies: association studies aim to find disease-predisposing alleles at the population level; and linkage studies focus on familial segregation. Although both strategies have compelling strengths, association analyses are more widely done and likely to spread even further in the future, especially in the pharmacogenetics domain. 5 Technical developments in molecular genetics facilitate these studies, as does use of gene-specific variants derived from the human genome sequencing project. 10 Furthermore, extensive catalogues of anonymous DNA sequence variants across the human genome are being compiled. 11,12 Some large-scale, population-based human samples have been, or are expected to be, gathered (eg, and use of DNA variants in drug development is expanding. 4 Coupling of high-throughput molecular technology, many genetic variants, and population-based samples offers unique opportunities for understanding the cause of common diseases. Genetic variants—or polymorphisms—arise from new mutations. The simplest type of polymorphism is a single base mutation, which substitutes one nucleotide for another, referred to as a single nucleotide polymorphism (SNP). SNPs do not necessarily have any relevance to disease or outcome; they can be anonymous variants within or between genes (ie, uncharacterised with respect to protein coding or gene function), or could be functional, causal mutations. More SNPs are thought to exist in the human genome than any other type of polymorphism. 20 Nearly three million variants have been reported and are catalogued in a public database In this review, we restrict our attention to SNPs, owing to their widespread presence and use, but the issues and principles described are general and apply to other DNA polymorphisms. Genetic association studies aim to correlate differences in disease frequencies between groups (or in trait levels for continuously varying characters) with differences in allele frequencies at an SNP. Thus, the frequencies of the two variant forms (alleles) of an SNP are of primary interest for identification of genes affecting disease. The simplest study design for assessment of genotype-phenotype correlation …