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Am J Hum Genet DOI:10.1016/j.ajhg.2014.03.019

Simulation of Finnish population history, guided by empirical genetic data, to assess power of rare-variant tests in Finland.

Publication TypeJournal Article
Year of Publication2014
AuthorsWang, SR, Agarwala, V, Flannick, J, Chiang, CWK, Altshuler, D, Hirschhorn, JN
Corporate AuthorsGoT2D Consortium
JournalAm J Hum Genet
Date Published2014 May 01
KeywordsComputer Simulation, Diabetes Mellitus, Type 2, European Continental Ancestry Group, Exome, Finland, Founder Effect, Humans, Models, Genetic, Multifactorial Inheritance, Population

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.


Alternate JournalAm. J. Hum. Genet.
PubMed ID24768551
PubMed Central IDPMC4067550
Grant ListF32 GM106656 / GM / NIGMS NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
R01 DK075787 / DK / NIDDK NIH HHS / United States
F32GM106656 / GM / NIGMS NIH HHS / United States
RC2 DK088389 / DK / NIDDK NIH HHS / United States
T32GM008313 / GM / NIGMS NIH HHS / United States
T32GM007748-33 / GM / NIGMS NIH HHS / United States
T32 GM008313 / GM / NIGMS NIH HHS / United States
2R01DK075787 / DK / NIDDK NIH HHS / United States
T32GM007753 / GM / NIGMS NIH HHS / United States
T32 GM007748 / GM / NIGMS NIH HHS / United States
1RC2DK088389-01 / DK / NIDDK NIH HHS / United States