1. Simulation of Finnish population history, guided by empirical genetic data, to assess power of rare-variant tests in Finland
- Author
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Mark A. DePristo, Gil McVean, Jacquelyn Murphy, Kyle J. Gaulton, Jasmina Kravic, Martin Hrabé de Angelis, Noël P. Burtt, Ryan Poplin, Jeff Chen, Peter S. Chines, Tiinamaija Toumi, David Buck, Khalid Shakir, Pierre Fontanillas, Richard N. Bergman, Neil Robertson, Leif Groop, Tim M. Strom, Martina Müller-Nurasyid, Loukas Moutsianas, Christian Fuchsberger, Charleston W. K. Chiang, Thomas Meitinger, Jennifer Kriebel, Richard D. Pearson, Christa Meisinger, Gonçalo R. Abecasis, Jaakko Tuomilehto, Ashok Kumar, Janina S. Ried, Anubha Mahajan, Andrew T. Hattersley, Adam E. Locke, Wolfgang Rathmann, Inga Prokopenko, Adrian Tan, Annette Peters, Lori L. Bonnycastle, Andrew D. Morris, Christopher Hartl, Peter Donnelly, Vineeta Agarwala, Will Rayner, Jason Flannick, Timothy M. Frayling, Cornelia Huth, Martijn van de Bunt, David Altshuler, Harald Grallert, Stacey Gabriel, Michael Boehnke, Laura J. Scott, Tim D. Spector, Thomas W. Blackwell, Heather M. Stringham, Phoenix Kwan, Alisa Manning, Tanya M. Teslovich, Sophie R. Wang, Jeroen R. Huyghe, Francis S. Collins, Kerrin S. Small, Cecilia M. Lindgren, Gerton Lunter, Mark I. McCarthy, Joel N. Hirschhorn, Timothy Fennell, Todd Green, Clement Ma, Manny Rivas, Claes Ladenvall, Bo Isomaa, Anne U. Jackson, Hyun Min Kang, Eric Banks, Michael L. Stitzel, Xueling Sim, John R. B. Perry, Bryan Howie, Konstantin Strauch, Goo Jun, Karen L. Mohlke, and Christian Gieger
- Subjects
Genetics ,Multifactorial Inheritance ,Models, Genetic ,Population ,Population genetics ,Biology ,Genetic architecture ,Founder Effect ,White People ,Article ,Diabetes Mellitus, Type 2 ,Evolutionary biology ,Genetic model ,Humans ,Genetics(clinical) ,Computer Simulation ,Exome ,Genotyping ,Genetics (clinical) ,Exome sequencing ,Finland ,Genetic association ,Founder effect - Abstract
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.
- Published
- 2013