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

Wang, Sophie R ; Agarwala, Vineeta ; Flannick, Jason ; Chiang, Charleston W K ; Altshuler, David and Hirschhorn, Joel N (2014) In American Journal of Human Genetics 94(5). p.20-710
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... (More)

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.

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author
; ; ; ; and
contributor
LU
author collaboration
organization
publishing date
type
Contribution to journal
publication status
published
keywords
Computer Simulation, Diabetes Mellitus, Type 2/genetics, European Continental Ancestry Group/genetics, Exome/genetics, Finland, Founder Effect, Humans, Models, Genetic, Multifactorial Inheritance/genetics, Population/genetics
in
American Journal of Human Genetics
volume
94
issue
5
pages
11 pages
publisher
Cell Press
external identifiers
  • pmid:24768551
  • scopus:84899921864
ISSN
0002-9297
DOI
10.1016/j.ajhg.2014.03.019
language
English
LU publication?
yes
id
b2639d36-4b1b-46e6-bc3f-47a4145205e5
date added to LUP
2019-01-21 10:15:29
date last changed
2021-08-11 02:04:14
@article{b2639d36-4b1b-46e6-bc3f-47a4145205e5,
  abstract     = {<p>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. </p>},
  author       = {Wang, Sophie R and Agarwala, Vineeta and Flannick, Jason and Chiang, Charleston W K and Altshuler, David and Hirschhorn, Joel N},
  issn         = {0002-9297},
  language     = {eng},
  month        = {05},
  number       = {5},
  pages        = {20--710},
  publisher    = {Cell Press},
  series       = {American Journal of Human Genetics},
  title        = {Simulation of Finnish population history, guided by empirical genetic data, to assess power of rare-variant tests in Finland},
  url          = {http://dx.doi.org/10.1016/j.ajhg.2014.03.019},
  doi          = {10.1016/j.ajhg.2014.03.019},
  volume       = {94},
  year         = {2014},
}