The impact of a fine-scale population stratification on rare variant association test results

PLoS One. 2018 Dec 6;13(12):e0207677. doi: 10.1371/journal.pone.0207677. eCollection 2018.

Abstract

Population stratification is a well-known confounding factor in both common and rare variant association analyses. Rare variants tend to be more geographically clustered than common variants, because of their more recent origin. However, it is not yet clear if population stratification at a very fine scale (neighboring administrative regions within a country) would lead to statistical bias in rare variant analyses. As the inclusion of convenience controls from external studies is indeed a common procedure, in order to increase the power to detect genetic associations, this problem is important. We studied through simulation the impact of a fine scale population structure on different rare variant association strategies, assessing type I error and power. We showed that principal component analysis (PCA) based methods of adjustment for population stratification adequately corrected type I error inflation at the largest geographical scales, but not at finest scales. We also showed in our simulations that adding controls obviously increased power, but at a considerably lower level when controls were drawn from another population.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bias
  • Computer Simulation
  • Gene Frequency
  • Genetic Association Studies / statistics & numerical data*
  • Genetic Predisposition to Disease
  • Genetic Variation*
  • Genetics, Population / statistics & numerical data*
  • Human Migration / statistics & numerical data
  • Humans
  • Models, Genetic
  • Polymorphism, Single Nucleotide
  • Population Groups / statistics & numerical data*
  • Principal Component Analysis

Grants and funding

This work was supported by a grant from The French Regional Council of Pays de la Loire (RFI VaCaRMe: Recherche, Formation et Innovation, Vaincre les maladies Cardiovaculaires, Respiratoires et Métaboliques) (CD, LB, and RR and funded Dr. Elodie Persyn). The website for this project is available at the following URL address http://www.vacarme-project.org/. Agence Nationale de la Recherche (ANR-15-CE17-0008-01 to RR): Grant Recipient was Richard Redon and funded scientist was Dr Elodie Persyn.