Human genetics of infectious diseases: a unified theory

Abstract

Since the early 1950s, the dominant paradigm in the human genetics of infectious diseases postulates that rare monogenic immunodeficiencies confer vulnerability to multiple infectious diseases (one gene, multiple infections), whereas common infections are associated with the polygenic inheritance of multiple susceptibility genes (one infection, multiple genes). Recent studies, since 1996 in particular, have challenged this view. A newly recognised group of primary immunodeficiencies predisposing the individual to a principal or single type of infection is emerging. In parallel, several common infections have been shown to reflect the inheritance of one major susceptibility gene, at least in some populations. This novel causal relationship (one gene, one infection) blurs the distinction between patient-based Mendelian genetics and population-based complex genetics, and provides a unified conceptual frame for exploring the molecular genetic basis of infectious diseases in humans.

Figure 1

Human genetics of infectious diseases. The spectrum of genetic predisposition to infectious diseases in human patients is represented, according to the number of genes involved (x-axis) and the number of infections (y-axis). The dominant view in human genetics of infectious diseases postulates that rare, ‘conventional', monogenic primary immunodeficiencies (PIDs, in green) predispose the individual to numerous infections (one gene, multiple infections), whereas common infectious diseases are associated with polygenic inheritance (in red) of numerous susceptibility genes (one infection, multiple genes). Novel monogenic PIDs (in yellow/green) predispose the individual to a principal or single type of infection. Major genes (in yellow/red) exert a nearly Mendelian impact at the population level and largely account for common infectious diseases in some individuals. The recent discovery of such human genes conferring vulnerability or resistance to a specific infection at the individual level (one gene, one infection) bridges the gap between the two classical fields of conventional PIDs and polygenic inheritance, as defined in the 50 s. As an example, genetic predisposition to tuberculosis, which was considered to be purely polygenic, was recently shown to reflect both new PID and major gene effects, at least in some patients (see text for details). Overall, these observations provide experimental support for a continuous spectrum of predisposition and a unified theory of the human genetics of infectious diseases.