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Sunday, December 26, 2010

Direct assessment of multiple testing correction in case-control association studies with related individuals

Genome-wide association studies typically test large numbers of genetic variants in association with trait values. 

It is well known that linkage disequilibrium (LD) between nearby markers tends to introduce correlation among association tests. Failure to properly adjust for multiple comparisons can lead to false-positive results or missing true-positive signals. 

The Bonferroni correction is generally conservative in the presence of LD. The permutation procedure, although has been widely employed to adjust for correlated tests, is not applicable when related individuals are included in case-control samples. 

With related individuals, the dependence among relatives' genotypes can also contribute to the correlation between tests.

We present a new method Pnorm to correct for multiple hypothesis testing in case-control association studies in which some individuals are related. The adjustment with Pnorm simultaneously accounts for two sources of correlations of the test statistics: (1) LD among genetic markers (2) dependence among genotypes across related individuals. 

Using simulated data based on the International HapMap Project, we demonstrate that it has better control of type I error and is more powerful than some of the recently developed methods. 

We apply the method to a genome-wide association study of alcoholism in the GAW 14 COGA data set and detect genome-wide significant association. 

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