Current projects

Through our research, we strive to answer the following questions: 1- What are the human genetic variants underlying susceptibility and resistance to specific pathogens? 2- What are the molecular mechanisms connecting these variants to cellular functions and immune responses? and 3- How do differences in population history and demography play into susceptibility and resistance to specific pathogens? You can find descriptions of current projects and examples from our past research related to each of these questions below.

Identification of human genetic factors underlying susceptibility to bacterial sepsis

Bacterial sepsis is a leading cause of morbidity worldwide. Theoretically, the majority of sepsis deaths are preventable through timely and appropriate clinical management. However, in most cases, non-specific symptoms make it difficult to separate sepsis from less severe infections in time. Similar to other infectious diseases, susceptibility to sepsis is in part driven by human genetic factors. In fact, previous human genetic studies of bacterial sepsis have identified several rare genetic variants in key immune genes that can increase disease risk. On the other hand, our understanding of common genetic variants that contribute to sepsis risk is limited. Larger, better-powered human genetics studies are required to identify such variants. To fill this gap, we are leading the largest human genomics study on bacterial sepsis (with so far over 9,000 cases and 700,000 controls). In the next step, we will use the results to develop a genetic risk score for sepsis in order to stratify low-risk from high-risk individuals prior to symptom development. This project is a collaboration between our team and several other groups and biobanks from around the world.

Some of our previous work on the identification of infectious disease risk variants:

Asgari, S., Schlapbach, L. J., Anchisi, S., Hammer, C., Bartha, I., Junier, T., Mottet-Osman, G., Posfay-Barbe, K. M., Longchamp, D., Stocker, M., Cordey, S., Kaiser, L., Riedel, T., Kenna, T., Long, D., Schibler, A., Telenti, A., Tapparel, C., McLaren, P. J., … Fellay, J. (2017). Severe viral respiratory infections in children with IFIH1 loss-of-function mutations. PNAS, 114(31), 8342–8347.

Asgari, S., McLaren, P. J., Peake, J., Wong, M., Wong, R., Bartha, I., Francis, J. R., Abarca, K., Gelderman, K. A., Agyeman, P., Aebi, C., Berger, C., Fellay, J., Schlapbach, L. J., & Swiss Pediatric Sepsis Study. (2016). Exome Sequencing Reveals Primary Immunodeficiencies in Children with Community-Acquired Pseudomonas aeruginosa Sepsis. Frontiers in Immunology, 7, 357.

Understanding the role of genetic ancestry in susceptibility to infectious diseases

It is well-established that differences in genetic ancestry can affect human traits. Infectious diseases are even more likely to be affected by population-level genetic differences because pathogens are a major evolutionary force in shaping our genome and they are usually restricted to specific geographical regions. This hypothesis is now supported by both evolutionary genomics and experimental immunology data. However, similar to many other diseases, the majority of large-scale infectious disease genomics studies are done in populations of European ancestry, limiting both our understanding of the human genetics of infectious diseases as well as the clinical application of findings. To fill this gap, we are leveraging the genetic diversity of our biobank, BioMe, to conduct admixture mapping for several infectious diseases in order to identify infectious disease loci that confer different risks in different populations. In the next stage, we will use our admixture mapping results to perform fine-mapping and functional follow-up to connect these risk loci to specific genetic variants and their function.

Some of our previous work on the role of genetic ancestry in complex traits:

Asgari, S., Luo, Y., Akbari, A., Belbin, G. M., Li, X., Harris, D. N., Selig, M., Bartell, E., Calderon, R., Slowikowski, K., Contreras, C., Yataco, R., Galea, J. T., Jimenez, J., Coit, J. M., Farroñay, C., Nazarian, R. M., O’Connor, T. D., Dietz, H. C., … Raychaudhuri, S. (2020). A positively selected FBN1 missense variant reduces height in Peruvian individuals. Nature, 582(7811), 234–239.

Asgari, S., Luo, Y., Huang, C.-C., Zhang, Z., Calderon, R., Jimenez, J., Yataco, R., Contreras, C., Galea, J. T., Lecca, L., Jones, D., Moody, D. B., Murray, M. B., & Raychaudhuri, S. (2022). Higher native Peruvian genetic ancestry proportion is associated with tuberculosis progression risk. Cell Genomics, 2(7), 100151.

Connecting infectious disease genetic susceptibility to immune functions

For most genetic variants identified to date, the biological mechanisms that connect them to cellular functions are not known. Similarly, for most genetic risk scores the cellular mechanisms and functions that differ between high- and low-risk individuals are yet to be identified. Filling this gap is pivotal for the development of new preventive and therapeutic measures. To this end, we collect blood immune cells from individuals carrying specific infectious disease risk variants and compare the gene expression profile in these cells with similar cells from individuals that do not carry the risk variants. We do these comparisons at baseline as well upon longitudinal stimulation with the relevant pathogens/antigens. Similarly, we compare the gene expression profiles of individuals with high and low genetic risk for specific infectious diseases and pre- and post-stimulation.

Some of our previous work on using gene expression to connect variants to function:

Nathan, A., Asgari, S., Ishigaki, K., Valencia, C., Amariuta, T., Luo, Y., Beynor, J. I., Baglaenko, Y., Suliman, S., Price, A. L., Lecca, L., Murray, M. B., Moody, D. B., & Raychaudhuri, S. (2022). Single-cell eQTL models reveal dynamic T cell state dependence of disease loci. Nature. https://doi.org/10.1038/s41586-022-04713-1