TY - JOUR
T1 - GWAS significance thresholds for deep phenotyping studies can depend upon minor allele frequencies and sample size
AU - Asif, Huma
AU - Alliey-Rodriguez, Ney
AU - Keedy, Sarah
AU - Tamminga, Carol A.
AU - Sweeney, John A.
AU - Pearlson, Godfrey
AU - Clementz, Brett A.
AU - Keshavan, Matcheri S.
AU - Buckley, Peter
AU - Liu, Chunyu
AU - Neale, Benjamin
AU - Gershon, Elliot S.
N1 - Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021/6
Y1 - 2021/6
N2 - An important issue affecting genome-wide association studies with deep phenotyping (multiple correlated phenotypes) is determining the suitable family-wise significance threshold. Straightforward family-wise correction (Bonferroni) of p < 0.05 for 4.3 million genotypes and 335 phenotypes would give a threshold of p < 3.46E−11. This would be too conservative because it assumes all tests are independent. The effective number of tests, both phenotypic and genotypic, must be adjusted for the correlations between them. Spectral decomposition of the phenotype matrix and LD-based correction of the number of tested SNPs are currently used to determine an effective number of tests. In this paper, we compare these calculated estimates with permutation-determined family-wise significance thresholds. Permutations are performed by shuffling individual IDs of the genotype vector for this dataset, to preserve correlation of phenotypes. Our results demonstrate that the permutation threshold is influenced by minor allele frequency (MAF) of the SNPs, and by the number of individuals tested. For the more common SNPs (MAF > 0.1), the permutation family-wise threshold was in close agreement with spectral decomposition methods. However, for less common SNPs (0.05 < MAF ≤ 0.1), the permutation threshold calculated over all SNPs was off by orders of magnitude. This applies to the number of individuals studied (here 777) but not to very much larger numbers. Based on these findings, we propose that the threshold to find a particular level of family-wise significance may need to be established using separate permutations of the actual data for several MAF bins.
AB - An important issue affecting genome-wide association studies with deep phenotyping (multiple correlated phenotypes) is determining the suitable family-wise significance threshold. Straightforward family-wise correction (Bonferroni) of p < 0.05 for 4.3 million genotypes and 335 phenotypes would give a threshold of p < 3.46E−11. This would be too conservative because it assumes all tests are independent. The effective number of tests, both phenotypic and genotypic, must be adjusted for the correlations between them. Spectral decomposition of the phenotype matrix and LD-based correction of the number of tested SNPs are currently used to determine an effective number of tests. In this paper, we compare these calculated estimates with permutation-determined family-wise significance thresholds. Permutations are performed by shuffling individual IDs of the genotype vector for this dataset, to preserve correlation of phenotypes. Our results demonstrate that the permutation threshold is influenced by minor allele frequency (MAF) of the SNPs, and by the number of individuals tested. For the more common SNPs (MAF > 0.1), the permutation family-wise threshold was in close agreement with spectral decomposition methods. However, for less common SNPs (0.05 < MAF ≤ 0.1), the permutation threshold calculated over all SNPs was off by orders of magnitude. This applies to the number of individuals studied (here 777) but not to very much larger numbers. Based on these findings, we propose that the threshold to find a particular level of family-wise significance may need to be established using separate permutations of the actual data for several MAF bins.
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U2 - 10.1038/s41380-020-0670-3
DO - 10.1038/s41380-020-0670-3
M3 - Article
C2 - 32066829
AN - SCOPUS:85079731498
SN - 1359-4184
VL - 26
SP - 2048
EP - 2055
JO - Molecular psychiatry
JF - Molecular psychiatry
IS - 6
ER -