Leveraging population differences to learn about the genetic basis of susceptibility to infectious diseases

This talk will take place via Microsoft Teams. Please turn off your video sharing and mute your microphones for the duration of the meeting. Paste this address into your browser to join: https://teams.microsoft.com/_#/l/meetup-join/19:meeting_ZTY2ZjA0MTMtNmJhNi00N2MyLTlkMjEtZTJmZDJmZDYwOWU3@thread.v2/0?context=%7B%22Tid%22:%22cc95de1b-97f5-4f93-b4ba-fe68b852cf91%22,%22Oid%22:%22faee8eaf-f9bf-478e-9151-5bbfc3b39a0f%22%7D&anon=true&deeplinkId=ab9004c4-8b2c-4c8e-d7b6-03630fa23610

Currently, human genetic studies, and in particular large-scale studies of complex traits, are conducted predominantly in Europeans. Expanding genetic studies to other populations is critical for discovering novel risk loci, fully understanding the genetic architecture of complex traits, and using genetic risk prediction in the clinical setting.

Human genetics of infectious diseases can in particular benefit from studies in diverse populations. Infectious diseases are a global health challenge with the highest burden falling on non-European populations. It is well-established that host genetic factors contribute significantly to inter-individual variability in infectious disease outcomes. Moreover, differences in population history can lead to population-level variations in susceptibility to specific pathogens, further highlighting the need to include diverse populations in host genetic studies.

In this talk, I will discuss how differences in genetic ancestry can be leveraged to learn about the genetic basis of complex traits. Specifically, I will share examples from our recently published work on genetics of height which led to the discovery of a novel, population-specific variant that reduces height by 2.2 cm per allele (Asgari, et. al, Nature, 2020). I will also share results from our ongoing work on the role of Native Peruvian ancestry in susceptibility to tuberculosis (TB) showing that Native ancestry can increase TB progression risk independently of socio-demographic and environmental confounders.

While host genetic studies can inform us about the genetic variants underlying susceptibility to specific pathogens, they cannot determine the cellular mechanisms by which these variants excerpt their effect. I will discuss this point in detail by giving an example from our work on the genetic basis of susceptibility to viral respiratory infections (Asgari, et. al, PNAS, 2017). In this study, we combined exome and RNA-sequencing with in vitro functional assays to identify and characterize loss-of-function variants causing extreme susceptibility to common respiratory viruses.

To conclude, I will present the prospects and some of the challenges associated with host genetic studies, particularly in underrepresented populations. I will discuss how the frameworks that I discussed above can be applied to future human genetic studies of infectious diseases in order to improve understanding of the biological processes involved in immunity, facilitate drug development, and reduce health disparities.