• age-related macular degeneration;
  • Complement Factor H gene;
  • GXE;
  • GWAS;
  • LBL;
  • MCMC;
  • missing heritability;
  • rare variants;
  • regularization;
  • retrospective likelihood


Two important contributors to missing heritability are believed to be rare variants and gene-environment interaction (GXE). Thus, detecting GXE where G is a rare haplotype variant (rHTV) is a pressing problem. Haplotype analysis is usually the natural second step to follow up on a genomic region that is implicated to be associated through single nucleotide variants (SNV) analysis. Further, rHTV can tag associated rare SNV and provide greater power to detect them than popular collapsing methods. Recently we proposed Logistic Bayesian LASSO (LBL) for detecting rHTV association with case–control data. LBL shrinks the unassociated (especially common) haplotypes toward zero so that an associated rHTV can be identified with greater power. Here, we incorporate environmental factors and their interactions with haplotypes in LBL. As LBL is based on retrospective likelihood, this extension is not trivial. We model the joint distribution of haplotypes and covariates given the case–control status. We apply the approach (LBL-GXE) to the Michigan, Mayo, AREDS, Pennsylvania Cohort Study on Age-related Macular Degeneration (AMD). LBL-GXE detects interaction of a specific rHTV in CFH gene with smoking. To the best of our knowledge, this is the first time in the AMD literature that an interaction of smoking with a specific (rather than pooled) rHTV has been implicated. We also carry out simulations and find that LBL-GXE has reasonably good powers for detecting interactions with rHTV while keeping the type I error rates well controlled. Thus, we conclude that LBL-GXE is a useful tool for uncovering missing heritability.