Lowe Jennifer K, Maller Julian B, Pe'er Itsik, Neale Benjamin M, Salit Jacqueline, Kenny Eimear E, Shea Jessica L, Burkhardt Ralph, Smith J Gustav, Ji Weizhen, Noel Martha, Foo Jia Nee, Blundell Maude L, Skilling Vita, Garcia Laura, Sullivan Marcia L, Lee Heather E, Labek Anna, Ferdowsian Hope, Auerbach Steven B, Lifton Richard P, Newton-Cheh Christopher, Breslow Jan L, Stoffel Markus, Daly Mark J, Altshuler David M, Friedman Jeffrey M
The Rockefeller University, New York, New York, USA.
PLoS Genet. 2009 Feb;5(2):e1000365. doi: 10.1371/journal.pgen.1000365. Epub 2009 Feb 6.
It has been argued that the limited genetic diversity and reduced allelic heterogeneity observed in isolated founder populations facilitates discovery of loci contributing to both Mendelian and complex disease. A strong founder effect, severe isolation, and substantial inbreeding have dramatically reduced genetic diversity in natives from the island of Kosrae, Federated States of Micronesia, who exhibit a high prevalence of obesity and other metabolic disorders. We hypothesized that genetic drift and possibly natural selection on Kosrae might have increased the frequency of previously rare genetic variants with relatively large effects, making these alleles readily detectable in genome-wide association analysis. However, mapping in large, inbred cohorts introduces analytic challenges, as extensive relatedness between subjects violates the assumptions of independence upon which traditional association test statistics are based. We performed genome-wide association analysis for 15 quantitative traits in 2,906 members of the Kosrae population, using novel approaches to manage the extreme relatedness in the sample. As positive controls, we observe association to known loci for plasma cholesterol, triglycerides, and C-reactive protein and to a compelling candidate loci for thyroid stimulating hormone and fasting plasma glucose. We show that our study is well powered to detect common alleles explaining >/=5% phenotypic variance. However, no such large effects were observed with genome-wide significance, arguing that even in such a severely inbred population, common alleles typically have modest effects. Finally, we show that a majority of common variants discovered in Caucasians have indistinguishable effect sizes on Kosrae, despite the major differences in population genetics and environment.
有人认为，在孤立的奠基者群体中观察到的有限遗传多样性和降低的等位基因异质性有助于发现导致孟德尔疾病和复杂疾病的基因座。强烈的奠基者效应、严重的隔离和大量近亲繁殖显著降低了密克罗尼西亚联邦科斯雷岛原住民的遗传多样性，这些原住民肥胖和其他代谢紊乱的患病率很高。我们假设，科斯雷岛上的遗传漂变以及可能的自然选择可能增加了以前罕见但具有相对较大效应的遗传变异的频率，使得这些等位基因在全基因组关联分析中易于检测到。然而，在大型近亲队列中进行基因定位带来了分析挑战，因为受试者之间广泛的亲缘关系违反了传统关联检验统计所基于的独立性假设。我们对科斯雷岛人群的2906名成员的15个数量性状进行了全基因组关联分析，使用新方法来处理样本中的极端亲缘关系。作为阳性对照，我们观察到与血浆胆固醇、甘油三酯和C反应蛋白的已知基因座以及促甲状腺激素和空腹血糖的一个引人注目的候选基因座存在关联。我们表明，我们的研究有足够的能力检测解释≥5%表型变异的常见等位基因。然而，在全基因组显著性水平上未观察到如此大的效应，这表明即使在这样一个严重近亲繁殖的人群中，常见等位基因通常也只有适度的效应。最后，我们表明，尽管在群体遗传学和环境方面存在重大差异，但在高加索人中发现的大多数常见变异对科斯雷岛人群的效应大小难以区分。
