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A Likelihood Ratio‐Based Mann‐Whitney Approach Finds Novel Replicable Joint Gene Action for Type 2 Diabetes
Author(s) -
Lu Qing,
Wei Changshuai,
Ye Chengyin,
Li Ming,
Elston Robert C.
Publication year - 2012
Publication title -
genetic epidemiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.301
H-Index - 98
eISSN - 1098-2272
pISSN - 0741-0395
DOI - 10.1002/gepi.21651
Subject(s) - single nucleotide polymorphism , genome wide association study , locus (genetics) , multiple comparisons problem , mann–whitney u test , genome , univariate , genetics , gene , computational biology , biology , genotype , statistics , mathematics , multivariate statistics
The potential importance of the joint action of genes, whether modeled with or without a statistical interaction term, has long been recognized. However, identifying such action has been a great challenge, especially when millions of genetic markers are involved. We propose a likelihood ratio‐based Mann‐Whitney test to search for joint gene action either among candidate genes or genome‐wide. It extends the traditional univariate Mann‐Whitney test to assess the joint association of genotypes at multiple loci with disease, allowing for high‐order statistical interactions. Because only one overall significance test is conducted for the entire analysis, it avoids the issue of multiple testing. Moreover, the approach adopts a computationally efficient algorithm, making a genome‐wide search feasible in a reasonable amount of time on a high performance personal computer. We evaluated the approach using both theoretical and real data. By applying the approach to 40 type 2 diabetes (T2D) susceptibility single‐nucleotide polymorphisms (SNPs), we identified a four‐locus model strongly associated with T2D in the Wellcome Trust (WT) study (permutation P ‐value < 0.001), and replicated the same finding in the Nurses’ Health Study/Health Professionals Follow‐Up Study (NHS/HPFS) ( P ‐value = 3.03 × 10 − 11). We also conducted a genome‐wide search on 385,598 SNPs in the WT study. The analysis took approximately 55 hr on a personal computer, identifying the same first two loci, but overall a different set of four SNPs, jointly associated with T2D ( P ‐value = 1.29 × 10 − 5). The nominal significance of this same association reached 4.01 × 10 − 6in the NHS/HPFS. Genet. Epidemiol. 00:1‐11, 2012. © 2012 Wiley Periodicals, Inc.