Assessing the impact of population stratification on genetic association studies.
Population stratification refers to differences in allele frequencies between cases and controls due to systematic differences in ancestry rather than association of genes with disease. It has been proposed that false positive associations due to stratification can be controlled by genotyping a few dozen unlinked genetic markers. To assess stratification empirically, we analyzed data from 11 case-control and case-cohort association studies. We did not detect statistically significant evidence for stratification but did observe that assessments based on a few dozen markers lack power to rule out moderate levels of stratification that could cause false positive associations in studies designed to detect modest genetic risk factors. After increasing the number of markers and samples in a case-cohort study (the design most immune to stratification), we found that stratification was in fact present. Our results suggest that modest amounts of stratification can exist even in well designed studies.
Freedman
Matthew L
ML
Department of Medicine and Molecular Biology, Massachusetts General Hospital, Boston, and Program in Medical and Population Genetics, Broad Institute, Cambridge, USA.
Reich
David
D
Penney
Kathryn L
KL
McDonald
Gavin J
GJ
Mignault
Andre A
AA
Patterson
Nick
N
Gabriel
Stacey B
SB
Topol
Eric J
EJ
Smoller
Jordan W
JW
Pato
Carlos N
CN
Pato
Michele T
MT
Petryshen
Tracey L
TL
Kolonel
Laurence N
LN
Lander
Eric S
ES
Sklar
Pamela
P
Henderson
Brian
B
Hirschhorn
Joel N
JN
Altshuler
David
D
D016022:Case-Control Studies; D015331:Cohort Studies; D005828:Genetics, Population; D006801:Humans; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide