Strategic approaches to unraveling genetic causes of cardiovascular diseases.
Strategic approaches to unraveling genetic causes of cardiovascular diseases.
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DOI：
10.1161/circresaha.110.236067
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发表时间：
2011-05-13
影响因子：
20.1
通讯作者：
Belmont J
中科院分区：
文献类型：
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作者：
Marian AJ;Belmont J
DNA序列变异（DSV）是几乎所有医学表型“因果场”的主要组成部分，无论是单基因家族性疾病还是没有明确家族聚集的复杂特征。单基因疾病的致病变异是必要且足以产生巨大影响的。相比之下，复杂的性状是由更复杂的贡献成分网络造成的，这些成分总体上增加了患病的可能性。识别单基因疾病致病变异的传统方法是遗传连锁。然而，它没有提供足够的分辨率来绘制小规模家族或散发病例中的致病基因。复杂性状的遗传学研究方法需要候选基因或全基因组关联研究（GWAS）。 GWAS 提供了对常见遗传变异影响的公正调查（常见疾病 - 常见变异假说）。 GWAS 已鉴定出多种心血管疾病的大量等位基因。然而，常见等位基因仅占性状总遗传力的相对较小部分。因此，焦点已转向鉴定可能产生更大效应的罕见变异（罕见变异-常见疾病假说）。大规模并行 DNA 测序平台的最新进展使这种转变成为可能，该平台提供了识别个体中几乎所有常见和罕见等位基因的机会。在这篇综述中，我们讨论了用于描述遗传对医学上重要的心血管表型的贡献的各种策略，强调了新的深度测序方法的实用性。
DNA sequence variants (DSVs) are major components of the “causal field” for virtually all-medical phenotypes, whether single-gene familial disorders or complex traits without a clear familial aggregation. The causal variants in single gene disorders are necessary and sufficient to impart large effects. In contrast, complex traits are due to a much more complicated network of contributory components that in aggregate increase the probability of disease. The conventional approach to identification of the causal variants for single gene disorders is genetic linkage. However, it does not offer sufficient resolution to map the causal genes in small size families or sporadic cases. The approach to genetic studies of complex traits entails candidate gene or Genome Wide Association Studies (GWAS). GWAS provides an unbiased survey of the effects of common genetic variants (common disease - common variant hypothesis). GWAS have led to identification of a large number of alleles for various cardiovascular diseases. However, common alleles account for a relatively small fraction of the total heritability of the traits. Accordingly, the focus has shifted toward identification of rare variants that might impart larger effect sizes (rare variant-common disease hypothesis). This shift is made feasible by recent advances in massively parallel DNA sequencing platforms, which afford the opportunity to identify virtually all common as well as rare alleles in individuals. In this review, we discuss various strategies that are used to delineate the genetic contribution to medically important cardiovascular phenotypes, emphasizing the utility of the new deep sequencing approaches.