Center for Research on Genomics and Global Health, National Human Genome Research Institute, Bethesda, Maryland, United States of America.
Genet Epidemiol. 2014 Apr;38(3):265-73. doi: 10.1002/gepi.21788. Epub 2014 Jan 26.
The National Human Genome Research Institute's catalog of published genome-wide association studies (GWAS) lists over 10,000 genetic variants collectively associated with over 800 human diseases or traits. Most of these GWAS have been conducted in European-ancestry populations. Findings gleaned from these studies have led to identification of disease-associated loci and biologic pathways involved in disease etiology. In multiple instances, these genomic findings have led to the development of novel medical therapies or evidence for prescribing a given drug as the appropriate treatment for a given individual beyond phenotypic appearances or socially defined constructs of race or ethnicity. Such findings have implications for populations throughout the globe and GWAS are increasingly being conducted in more diverse populations. A major challenge for investigators seeking to follow up genomic findings between diverse populations is discordant patterns of linkage disequilibrium (LD). We provide an overview of common measures of LD and opportunities for their use in novel methods designed to address challenges associated with following up GWAS conducted in European-ancestry populations in African-ancestry populations or, more generally, between populations with discordant LD patterns. We detail the strengths and weaknesses associated with different approaches. We also describe application of these strategies in follow-up studies of populations with concordant LD patterns (replication) or discordant LD patterns (transferability) as well as fine-mapping studies. We review application of these methods to a variety of traits and diseases.
美国国家人类基因组研究所（National Human Genome Research Institute）发布的全基因组关联研究（genome-wide association studies，GWAS）目录中，列出了超过 10000 个与 800 多种人类疾病或特征相关的遗传变异。这些 GWAS 大多是在欧洲血统人群中进行的。从这些研究中获得的发现，确定了与疾病相关的基因座和参与疾病病因的生物学途径。在许多情况下，这些基因组学发现导致了新型医学疗法的开发，或者为某些特定个体开具特定药物的处方提供了证据，而不仅仅是基于表型或种族或族裔的社会定义。这些发现对全球各地的人群都有影响，GWAS 也越来越多地在更多样化的人群中进行。对于试图在不同人群之间跟进基因组发现的研究人员来说，一个主要挑战是连锁不平衡（linkage disequilibrium，LD）模式的不一致。我们提供了 LD 的常用衡量标准概述，并介绍了在设计用于解决在非洲裔人群中跟进欧洲裔人群进行的 GWAS 相关挑战的新方法中使用这些标准的机会，或者更普遍地说，在 LD 模式不一致的人群之间。我们详细说明了不同方法的优缺点。我们还描述了这些策略在具有一致 LD 模式（复制）或不一致 LD 模式（可转移性）的人群的后续研究中的应用，以及精细映射研究。我们回顾了这些方法在各种特征和疾病中的应用。
