Case-Only Studies of Gene-Environment Interaction: Role of Linkage Disequilibrium and Population Stratification

Studies of gene-environment interactions (G×E) have been considered important owing to their scientific and public health implications. Indeed, many common complex diseases including inflammatory bowel disease (IBD) are presumed to rely on both genetic (G) and environmental (E) risk factors. One major challenge to G×E studies is the insufficient power of traditional epidemiological study designs. A nontraditional approach, the case-only (CO) design, has been proposed as a potentially efficient strategy to assess G×E. Previously, the CO approach was shown to provide better per-sample power compared to other epidemiological study designs including case-control or cohort designs. This approach relies upon two key assumptions, namely that (i) the disease is sufficiently rare in the general population and that (ii) G and E are uncorrelated in the general population. When these assumptions are valid, departures from a multiplicative relative risk model, colloquially known as a ‘multiplicative interaction’, can be evaluated by testing the association between G and E in cases only. Therefore, in contrast to case-control studies, CO studies require genotype and exposure information from a set of affected individuals alone (‘no controls’) to track down the underlying G×E. In the past, CO studies of G×E usually followed a candidate (or single-) gene approach, but their utility on genome-wide level remained unexplored