Gao X, Starmer J, Martin ER. A multiple testing correction method for ...

368 Gao et al.
the SNPs all together if the eigenvalues can be
derived. In the situations where the high dimensionality
prohibits the calculation of eigenvalues, we can
analyze the SNPs on each chromosome separately or
according to the gene functions and then sum all of
the Meff values together. The total Meff can be used to
calculate the adjusted PWER. In genome-wide
association studies, we have to partition the SNPs
into several parts and analyze them separately. Since
SNPs on different chromosomes are expected to be
in linkage equilibrium in general populations, the
genome-wide effective number of independent tests
can be obtained by summing the chromosome
specific Meff values. For each chromosome, we may
use the partition-ligation approach by dividing the
SNPs into several parts, and then sum the Meff
values from each partition, similar to how we tested
our Alzheimer SNP data set. The total Meff is used in
the final adjustment calculation. Due to the interblock
correlations that are unlikely to be captured in
this partition-ligation approach, the total Meff may
be slightly conservative. However, the interblock
correlations may be reduced if we partition SNPs
according to their haplotype block structure.
In summary, the simpleM algorithm provides a
highly accurate approximation to the permutationbased
correction threshold and is easily implemented.
Itisshowntobesimple,fastandmoreaccuratethan
recently developed methods and is comparable to the
permutation-based correction threshold using both
simulated and real SNP data. The efficiency and
accuracy of the simpleM method make it an attractive
choice for multiple testing adjustment when there is
high intermarker LD in the SNP data set as in
candidate gene or genome-wide association studies.
ACKNOWLEDGMENTS
This work was supported in part by NIH grants
NS39764, AG019757 and AG20135 and NIEHS T32
ES007126. We thank Dr. Gary Beecham who prepared
the Alzheimer data for us. We thank Dr.
Richard Morris for initial inspiration.
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