Tuberculosis as a complex trait: impact of genetic epidemiological study design.

Several studies have suggested a role for human genetic risk factors in the susceptibility to developing tuberculosis (TB). However, results of these studies have been inconsistent, and one potential reason for these inconsistencies is variation in aspects of study design. Specifically, phenotype definitions and population genetic factors have varied dramatically. Since TB is a complex trait, there are many challenges in designing studies to assess appropriately human genetic risk factors for the development of TB as opposed to the acquisition of latent M. tuberculosis infection. In this review we summarize these important study design differences, with illustrations from the TB genetics literature. We cite specific examples of studies of the NRAMP1 (SLC11A1) gene and present Fisher's combined p values for different stratifications of these studies to further illustrate the impact of study design differences. Finally, we provide suggestions for the design of future genetic epidemiological studies of TB.