Genetic Dissection of Complex Infection Phenotypes

Abstract: Mycobacteria are among the most medically important human pathogens. Susceptibility to mycobacterial disease and immune responses to mycobacterial infection are strongly heritable human traits. Yet, the genetic underpinnings of variability of the immune response and of variation in susceptibility to mycobacterial disease have been poorly investigated compared to non-infectious diseases of more limited global health importance. Here, I will review part of the genetic epidemiological studies that have been done to address the problem of susceptibility to infection with Mycobacterium tuberculosis, drawing in particular on our studies in high transmission settings for M. tuberculosis. Using the example of our studies, I will discuss the complexity of phenotype definition for M. tuberculosis infection. By extension to our genetic studies of the mycobacterial diseases tuberculosis and leprosy, I will discuss for two examples, age-at-onset and endo-phenotypes, how proper definition of phenotype has been key for the successful identification of disease susceptibility genes.