Methods for Genome-wide Association Studies in Admixed Populations

描述（由申请人提供）：全基因组关联研究（GWAS）已经成功地确定了导致疾病风险的常见遗传变异。然而，几乎所有这些研究都是在欧洲血统的人群中进行的。纳入其他人群是很重要的，因为欧洲人的GWAS不太可能检测到仅在非欧洲人群中常见的风险变异。在美国，大多数非欧洲血统的人属于混合人群（例如非洲裔美国人或拉丁美洲人），他们继承了多个大陆人口的祖先。现有的混合群体GWAS方法是不充分的，因为它们没有同时考虑SNP关联和混合关联信号。因此，如果应用现有的方法，分析将不能得到充分的支持，并且会错过重要的变量。对于已知存在人群差异的疾病，如非洲裔美国人的心血管疾病和拉丁裔美国人的哮喘，迫切需要开发结合这些信号的方法，因为混合关联信号可能特别重要。在此，我们建议开发一套完整的方法和软件来结合混合群体中GWAS中的SNP和混合关联信号，同时解决诸如归算和选择SNP进行复制等问题。我们的目标是使混合血统人群的关联研究与同质血统人群的研究一样实用。除了非裔美国人之外，我们还将开发复杂混合人群（例如拉丁美洲人）的方法，这些混合人群继承了三个或更多大陆人群的祖先，以及来自混合人群的相关个体。我们的研究方法将由经验数据驱动，包括超过10,000个非洲裔美国人样本和2,400个拉丁裔样本，这些样本将由CARe联盟、杰克逊心脏研究和多种族队列研究进行基因组扫描。我们的工作不仅适用于混合人群的GWAS，也适用于欧洲和混合人群的荟萃分析，以及未来基于测序的研究。

DESCRIPTION (provided by applicant): Genome-wide association studies (GWAS) have been successful in identifying common genetic variants contributing to disease risk. However, nearly all of these studies have been conducted in populations of European ancestry. It is important to include other populations, because GWAS in Europeans are unlikely to detect risk variants that are common only in non-European populations. In the United States, the majority of individuals of non-European ancestry belong to admixed populations (e.g. African Americans or Latinos) that inherit ancestry from more than one continental population. Existing GWAS methods for admixed populations are inadequate, because they do not incorporate both SNP association and admixture association signals. Thus, if existing methods are applied, analyses will not be fully powered and important variants will be missed. For diseases with known population differences-such as cardiovascular disease in African Americans and asthma in Latinos-the need to develop methods that combine these signals is particularly pressing, because admixture association signals are likely to be particularly important. Here, we propose to develop a complete set of methods and software to combine SNP and admixture association signals in GWAS in admixed populations, while addressing questions such as imputation and choosing SNPs for replication. Our goal is to make fully powered association studies in populations of mixed ancestry as practical as studies in populations of homogeneous ancestry. In addition to African Americans, we will also develop methods for complex admixed populations (e.g. Latinos) that inherit ancestry from three or more continental populations, and for related individuals from admixed populations. Our methods research will be driven by empirical data, including over 10,000 African American samples and 2,400 Latino samples that will be genome-scanned by the CARe consortium, the Jackson Heart Study, and the Multiethnic Cohort Study. Our work will be applicable not only to GWAS in admixed populations, but also to meta-analyses of European and admixed populations, as well as future resequencing-based studies.