Copyright © 2007 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 81, Issue 2, 234-242, 1 August 2007
doi:10.1086/519221
Article
Combining Evidence of Natural Selection with Association Analysis Increases Power to Detect Malaria-Resistance Variants
George Ayodoa, Alkes L. Pricea, Alon Keinana, Arthur Ajwangb, Michael F. Otienob, Alloys S.S. Oragob, Nick Pattersona and David Reicha, 
, 
a From the Department of Genetics, Harvard Medical School, and Broad Institute of Harvard and MIT, Boston
b Department of Pre-Clinical Sciences, Kenyatta University, Nairobi
Address for correspondence and reprints: Dr. David Reich, Harvard Medical School, Department of Genetics, 77 Avenue Louis Pasteur, New Research Building, Boston, MA 02115Abstract
Statistical power to detect disease variants can be increased by weighting candidates by their evidence of natural selection. To demonstrate that this theoretical idea works in practice, we performed an association study of 10 putative resistance variants in 471 severe malaria cases and 474 controls from the Luo in Kenya. We replicated associations at HBB (P=.0008) and CD36 (P=.03) but also showed that the same variants are unusually differentiated in frequency between the Luo and Yoruba (who historically have been exposed to malaria) and the Masai and Kikuyu (who have not been exposed). This empirically demonstrates that combining association analysis with evidence of natural selection can increase power to detect risk variants by orders of magnitude—up to P=.000018 for HBB and P=.00043 for CD36.
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