The bias introduced by population stratification in IBD based linkage analysis

Tao Wang, Robert C. Elston

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

The lack of replication of model-free linkage analyses performed on complex diseases raises questions about the robustness of these methods to various biases. The confounding effect of population stratification on a genetic association study has long been recognized in the genetic epidemiology community. Because the estimation of the number of alleles shared identical by descent (IBD) does not depend on the marker allele frequency when founders of families are observed, model-free linkage analysis is usually thought to be robust to population stratification. However, for common complex diseases, the genotypes of founders are often unobserved and therefore population stratification has the potential to impair model-free linkage analysis. Here, we demonstrate that, when some or all of the founder genotypes are missing, population stratification can introduce deleterious effects on various model-free linkage methods or designs. For an affected sib pair design, it can cause excess false-positive discoveries even when the trait distribution is homogeneous among subpopulations. After incorporating a control group of discordant sib pairs or for a quantitative trait, two circumstances must be met for population stratification to be a confounder: the distributions for both the marker and the trait must be heterogeneous among subpopulations. When this occurs, the bias can result in either a liberal, and hence invalid, test or a conservative test. Bias can be eliminated or alleviated by inclusion of founders' or other family members' genotype data. When this is not possible, new methods need to be developed to be robust to population stratification.

Original languageEnglish (US)
Pages (from-to)134-142
Number of pages9
JournalHuman Heredity
Volume60
Issue number3
DOIs
StatePublished - 2005
Externally publishedYes

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Population
Genotype
Molecular Epidemiology
Genetic Association Studies
Gene Frequency
Alleles
Control Groups

Keywords

  • Bias
  • Model-free linkage analysis
  • Population stratification

ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

The bias introduced by population stratification in IBD based linkage analysis. / Wang, Tao; Elston, Robert C.

In: Human Heredity, Vol. 60, No. 3, 2005, p. 134-142.

Research output: Contribution to journalArticle

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