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Letter
Nature Genetics  36, 388 - 393 (2004)
Published online: 28 March 2004; | doi:10.1038/ng1333

Assessing the impact of population stratification on genetic association studies

Matthew L Freedman1, 2, 3, 15, David Reich3, 4, 15, Kathryn L Penney1, 2, 3, Gavin J McDonald3, 4, Andre A Mignault4, Nick Patterson3, Stacey B Gabriel3, Eric J Topol5, Jordan W Smoller6, 7, Carlos N Pato8, 9, Michele T Pato8, 9, Tracey L Petryshen3, Laurence N Kolonel10, Eric S Lander3, 11, Pamela Sklar3, 6, 7, Brian Henderson12, Joel N Hirschhorn3, 4, 13 & David Altshuler1, 3, 4, 14

1  Departments of Medicine and Molecular Biology, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA.

2  Department of Hematology-Oncology, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA.

3  Program in Medical and Population Genetics, Broad Institute, One Kendall Square, Building 300, Cambridge, Massachusetts 02139, USA.

4  Department of Genetics, Harvard Medical School, New Research Building, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.

5  Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio, USA.

6  Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, USA.

7  Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, 149 13th Street, Charlestown, Massachusetts, USA.

8  Veterans Administration, Syracuse, New York, USA.

9  Center for Psychiatric and Molecular Genetics, SUNY/Upstate Medical University, Syracuse, New York, USA.

10  Cancer Etiology Program, Cancer Research Center of Hawaii, University of Hawaii, Honolulu, Hawaii, USA.

11  Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

12  Department of Preventative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.

13  Divisions of Genetics and Endocrinology, Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.

14  Diabetes Unit, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA.

15  These authors contributed equally to this work.

Correspondence should be addressed to David Reich reich@receptor.med.harvard.edu
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.


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Nature Genetics
ISSN: 1061-4036
EISSN: 1546-1718
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