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Genetic mapping of between-population variation using mapping by admixture linkage disequilibrium: Methodology and application to lipoprotein(a).

机译：使用混合连锁不平衡作图进行种群间变异的遗传作图：方法学和对脂蛋白的应用（a）。

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摘要

Most genetic association studies focus on within-population, rather than between-population, differences in disease susceptibility. While between-population variation accounts for only ∼5% of human genetic diversity, consequences for disease risk differences across populations are increasingly apparent. Mapping by Admixture Linkage Disequilibrium (MALD) has been proposed as a method for mapping the genetic basis for between-population disease differences when an admixed population is available with genetic contributions from higher-risk and lower-risk populations. The current restriction of study design considerations for MALD to family-based settings has limited application, since many diseases for which MALD could be appropriate occur later in life, when parental genotypes often are unavailable.; For this dissertation, explicit models of admixture dynamics were used to identify and investigate the relevant parameters for population-based MALD (Chapter 2). The resulting analytic strategy was applied to the heritable coronary heart disease risk factor lipoprotein(a) [Lp(a)] level, which is two-fold higher in African than non-African populations (Chapter 3). The etiology of the difference is unknown and has variously been attributed to environment, cis-acting variation at the apo(a) gene (LPA), and trans-acting factors. Analysis in 249 African-Americans and 534 European-Americans in the CHOICE Cohort strongly implicated LPA in higher African Lp(a). Further investigation of LPA candidate variants identified 3 single-nucleotide polymorphisms (SNPs) that explained 60% of the between-population Lp(a) level difference (Chapter 4). Each was uncommon in one or both populations, demonstrating that multiple rare alleles can generate large differences across populations. This suggests that alternative strategies to those currently being developed for genetic association studies—which assume universally common susceptibility—may be required for identifying the genetic basis for between-population risk variation.
机译：大多数遗传关联研究关注的是疾病易感性的种群内差异，而不是种群间差异。尽管种群间变异仅占人类遗传多样性的5％左右，但对人群间疾病风险差异的影响越来越明显。已经提出了通过混合连锁不平衡（MALD）进行作图的方法，该方法可在高风险和低风险人群具有遗传贡献的情况下，为种群间疾病差异的遗传基础作图。目前对于MALD的研究设计考虑仅限于基于家庭的环境，因为许多可能适合MALD的疾病会在以后的生活中发生，而通常无法获得父母的基因型。本文采用混合动力学的显式模型来识别和研究基于人群的MALD的相关参数（第2章）。所得的分析策略应用于可遗传的冠心病危险因素脂蛋白（a）[Lp（a）]水平，该水平在非洲比非非洲人群高两倍（第3章）。这种差异的病因尚不清楚，并且已被归因于环境，apo（a）基因（LPA）的顺式作用变异和 trans 作用因子。在CHOICE队列中对249名非裔美国人和534名欧洲裔美国人进行的分析强烈暗示了非洲高脂蛋白（a）中的 LPA 。对 LPA 候选变体的进一步研究确定了3个单核苷酸多态性（SNP），它们解释了人口之间Lp（a）水平差异的60％（第4章）。在一个或两个种群中，每种都不常见，这表明多个稀有等位基因可以在各个种群之间产生巨大差异。这表明，为了确定人群间风险差异的遗传基础，可能需要替代目前为遗传协会研究制定的替代策略（假定普遍具有普遍敏感性）。

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  • 作者

    Chretien, Jean-Paul.;

  • 作者单位

    The Johns Hopkins University.;

  • 授予单位 The Johns Hopkins University.;
  • 学科 Health Sciences Public Health.; Black Studies.; Biology Genetics.
  • 学位 Ph.D.
  • 年度 2003
  • 页码 p.660
  • 总页数 205
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 预防医学、卫生学;
  • 关键词

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