Originally published as Genetics Published Articles Ahead of Print on August 24, 2008.

Genetics, Vol. 180, 697-702, September 2008, Copyright © 2008
doi:10.1534/genetics.108.089839

A Weighted-Holm Procedure Accounting for Allele Frequencies in Genomewide Association Studies

Cyril Dalmasso^*, Emmanuelle Génin and David-Alexandre Trégouet^,,1

^* Université Paris-Sud, JE 2492, F-94807, Villejuif, France, INSERM, UMR_S 794, F-75010, Paris, France, INSERM, UMR_S 525, F-75013, Paris, France and UPMC Paris 06, UMR_S 525, F-75013, Paris, France

¹ Corresponding author: INSERM, UMR-S525, UPMC Paris 06, 91 Boulevard de l'Hopital, 75634 Paris Cedex 13, France.
E-mail: tregouet{at}chups.jussieu.fr

In the context of genomewide association studies where hundreds of thousand of polymorphisms are tested, stringent thresholds on the raw association test P-values are generally used to limit false-positive results. Instead of using thresholds based on raw P-values as in Bonferroni and sequential Sidak (SidakSD) corrections, we propose here to use a weighted-Holm procedure with weights depending on allele frequency of the polymorphisms. This method is shown to substantially improve the power to detect associations, in particular by favoring the detection of rare variants with high genetic effects over more frequent ones with lower effects.

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