Simulation of Finnish Population History, Guided by Empirical Genetic Data, to Assess Power of Rare-Variant Tests in Finland

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• 作者：Sophie R. Wang¹ ; ² ; ³ ; Vineeta Agarwala² ; ⁴ ; ⁵ ; Jason Flannick² ; ⁶ ; Charleston W.K. Chiang⁷ ; David Altshuler² ; ³ ; ⁶ ; ⁸ ; GoT2D Consortium ; Jason Flannick ; Alisa Manning ; Christopher Hartl ; Vineeta Agarwala ; Pierre Fontanillas ; Todd Green ; Eric Banks ; Mark DePristo ; Ryan Poplin ; Khalid Shakir ; Timothy Fennell ; Jacquelyn Murphy ; Noë ; l Burtt ; Stacey Gabriel ; David Altshuler ; Christian Fuchsberger ; Hyun Min Kang ; Xueling Sim ; Clement Ma ; Adam Locke ; Thomas Blackwell ; Anne Jackson ; Tanya Teslovich ; Heather Stringham ; Peter Chines ; Phoenix Kwan ; Jeroen Huyghe ; Adrian Tan ; Goo Jun ; Michael Stitzel ; Richard N. Bergman ; Lori Bonnycastle ; Jaakko Tuomilehto ; Francis S. Collins ; Laura Scott ; Karen Mohlke ; Gonç ; alo Abecasis ; Michael Boehnke ; Tim Strom ; Christian Gieger ; Martina Mü ; ller-Nurasyid ; Harald Grallert ; Jennifer Kriebel ; Janina Ried ; Martin Hrabé ; de Angelis ; Cornelia Huth ; Christa Meisinger ; Annette Peters ; Wolfgang Rathmann ; Konstantin Strauch ; Thomas Meitinger ; Jasmina Kravic ; Claes Ladenvall ; Tiinamaija Toumi ; Bo Isomaa ; Leif Groop ; Kyle Gaulton ; Loukas Moutsianas ; Manny Rivas ; Richard Pearson ; Anubha Mahajan ; Inga Prokopenko ; Ashish Kumar ; John Perry ; Jeff Chen ; Bryan Howie ; Martijn van de Bunt ; Kerrin Small ; Cecilia Lindgren ; Gerton Lunter ; Neil Robertson ; Will Rayner ; Andrew Morris ; David Buck ; Andrew Hattersley ; Tim Spector ; Gil McVean ; Tim Frayling ; Peter Donnelly ; Mark McCarthy
• 刊名：The American Journal of Human Genetics
• 出版年：1 May 2014
• 年：2014
• 卷：94
• 期：5
• 页码：710-720
• 全文大小：1176 K

文摘

Finnish samples have been extensively utilized in studying single-gene disorders, where the founder effect has clearly aided in discovery, and more recently in genome-wide association studies of complex traits, where the founder effect has had less obvious impacts. As the field starts to explore rare variants’ contribution to polygenic traits, it is of great importance to characterize and confirm the Finnish founder effect in sequencing data and to assess its implications for rare-variant association studies. Here, we employ forward simulation, guided by empirical deep resequencing data, to model the genetic architecture of quantitative polygenic traits in both the general European and the Finnish populations simultaneously. We demonstrate that power of rare-variant association tests is higher in the Finnish population, especially when variants’ phenotypic effects are tightly coupled with fitness effects and therefore reflect a greater contribution of rarer variants. SKAT-O, variable-threshold tests, and single-variant tests are more powerful than other rare-variant methods in the Finnish population across a range of genetic models. We also compare the relative power and efficiency of exome array genotyping to those of high-coverage exome sequencing. At a fixed cost, less expensive genotyping strategies have far greater power than sequencing; in a fixed number of samples, however, genotyping arrays miss a substantial portion of genetic signals detected in sequencing, even in the Finnish founder population. As genetic studies probe sequence variation at greater depth in more diverse populations, our simulation approach provides a framework for evaluating various study designs for gene discovery.