Journal
BIOMETRICS
Volume 73, Issue 1, Pages 344-355Publisher
WILEY
DOI: 10.1111/biom.12567
Keywords
G-E dependence; GXE; LBL; Missing heritability; Rare variants; Reversible jump MCMC
Funding
- National Cancer Institute, NIH [R03CA171011]
- National Science Foundation [DMS-1208968]
- Division Of Mathematical Sciences
- Direct For Mathematical & Physical Scien [1208968] Funding Source: National Science Foundation
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Finding rare variants and gene-environment interactions (GXE) is critical in dissecting complex diseases. We consider the problem of detecting GXE where G is a rare haplotype and E is a nongenetic factor. Such methods typically assume G-E independence, which may not hold in many applications. A pertinent example is lung cancer-there is evidence that variants on Chromosome 15q25.1 interact with smoking to affect the risk. However, these variants are associated with smoking behavior rendering the assumption of G-E independence inappropriate. With the motivation of detecting GXE under G-E dependence, we extend an existing approach, logistic Bayesian LASSO, which assumes G-E independence (LBL-GXE-I) by modeling G-E dependence through a multinomial logistic regression (referred to as LBL-GXE-D). Unlike LBL-GXE-I, LBL-GXE-D controls type I error rates in all situations; however, it has reduced power when G-E independence holds. To control type I error without sacrificing power, we further propose a unified approach, LBL-GXE, to incorporate uncertainty in the G-E independence assumption by employing a reversible jump Markov chain Monte Carlo method. Our simulations show that LBL-GXE has power similar to that of LBL-GXE-I when G-E independence holds, yet has well-controlled type I errors in all situations. To illustrate the utility of LBL-GXE, we analyzed a lung cancer dataset and found several significant interactions in the 15q25.1 region, including one between a specific rare haplotype and smoking.
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