The human immune system plays an important role in host protection, autoimmune and inflammatory diseases, cancer, metabolism, and ageing. Given this central role in many human pathologies, it is crucial to understand the variability of immune responses at the population level and how this variability relates to disease susceptibility.
Large genome-wide association studies have implicated hundreds of genetic loci in immune-related genes highlighting the immune system’s role in the biological mechanism underlying genetic risk to numerous diseases. However, for the vast majority of these genetic variants, we have little understanding of their functional effects and their context-specificity. Studying the genetic influence on immune response is further complicated by the complexity of the immune system, which consists of many different cell types that respond to a plethora of signals, interact with each other and induce different effector functions under diverse kinetics.
Our group integrates state-of-the-art genomic and functional genetic approaches to characterize the genetic basis of human immune response variation to advance our understanding of disease-associated variants and answer questions of genome function plasticity that is shaped by gene-by-environment interactions. We focus in particular on molecular quantitative traits (molQTLs) in the context of immune activation and disentangle the cell type and context specificity of functional genetic variants with the ultimate goal to develop a roadmap for complex traits at large and enable the move from genetic discovery to functional interpretation and ultimately clinical impact.
COVID-19 is an infectious disease caused by the new strain of coronavirus SARS-CoV-2. It was first identified in 2019 in Wuhan, China, and has since spread globally, resulting in the 2019–20 coronavirus pandemic. Common symptoms include fever and cough, however disease symptoms as well as disease course and outcome are highly variable ranging from asymptomatic cases to severe pneumonia and death. While children are likely to have milder symptoms than adults, children of all ages are susceptible to COVID-19 and can suffer from severe disease. Until now it is unknown why children show a different course of disease compared to adults.
Studying the immune response to SARS-CoV-2 in children is therefore critical to rapidly advance our understanding of the pathophysiology of COVID-19 both in children and adults. Children offer a unique possibility to study host-related factors that determine COVID-19 severity in the absence of ageing and comorbidity-related interactions, which are largely determining the disease course in adults.
We have therefore initiated a functional genetics and genomics COVID-19 study to examine the genetic and environmental risk factors of COVID-19 in pediatric and adult patients. Our group integrates deep immune profiling with multi-omics across multiple molecular levels (genome, transcriptome, proteome, metabolome) to enhance our understanding of the human immune response to SARS-CoV-2. Following questions will be addressed:
- Why does SARS-CoV-2 affect children differently compared to adults?
- What are the genetic and immunological risk factors that contribute to this difference?
- Can we use these factors to identify those children who will become severely affected?
As part of the Child Health Alliance Munich (CHANCE) initiative this prospective study is performed at the Dr. von Hauner Children’s Hospital of the Ludwig-Maximilians University (LMU) Munich and the Department of Pediatrics of the Technical University of Munich School of Medicine (TUM). The study is also actively involved in national (Deutsche COVID-19 OMICS Initiative) and international (COVID-19 Host Genetics Initiative) COVID-19 initiatives to join forces in combating this pandemic.
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3. Oliva, M.*, Muñoz-Aguirre, M.*, Kim-Hellmuth, S.*, Wucher, V., Gewirtz, A., Cotter, D., Parsana, P., Kasela, S., Balliu, B., Viñuela, A., Castel, S. E., Mohammadi, P., Aguet, F., Zou, Y., Khramtsova, E., Skol, A., Garrido-Martin, D., Reverter, F., Brown, A., Evans, P., Gamazon, E., Payne, A., Bonazzola, R., Barbeira, A. N., Hamel, A. R., Martinez-Perez, A., Soria, J. M., GTEx Consortium, Pierce, B., Stephens, M., Eskin, E., Dermitzakis, E., Segre, A. V., Im, H. K., Engelhardt, B., Ardlie, K. G., Montegomery, S., Battle, A., Lappalainen, T., Guigó, R. & Stranger, B. E. The impact of sex on gene expression and its genetic regulation across human tissues. Science 369 (2020). doi: 10.1126/science.aba3066
4. Demanelis, K., Jasmine, F., Chen, L. S., Chernoff, M., Tong, L., Delgado, D., Zhang, C., Shinkle, J., Sabarinathan, M., Lin, H., Ramirez, E., Oliva, M., Kim-Hellmuth, S., Stranger, B. E., Lai, T.-P., Aviv, A., Ardlie, K. G., Aguet, F., Ahsan, H., GTEx Consortium, Doherty, J. A., Kibriya, M. G. & Pierce, B. L. Determinants of telomere length across human tissues. Science 369 (2020). doi: 10.1126/science.aaz6876
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7. de Goede, O. M., Ferraro, N. M., Nachun, D. C., Rao, A. S., Aguet, F., Barbeira, A. N., Castel, S. E., Kim-Hellmuth, S., Park, Y., Scott, A. J., Strober, B. J., GTEx Consortium, Brown, C. D., Wen, X., Hall, I. M., Battle, A., Lappalainen, T., Im, H. K., Ardlie, K. G., Quertermous, T., Kirkegaard, K. & Montgomery, S. B. Long non-coding RNA gene regulation and trait associations across human tissues. bioRxiv 7, 1860–31 (2019).
8. Kim-Hellmuth, S.†, Bechheim, M., Pütz, B., Mohammadi, P., Nédélec, Y., Giangreco, N., Becker, J., Kaiser, V., Fricker, N., Beier, E., Boor, P., Castel, S. E., Nöthen, M. M., Barreiro, L. B., Pickrell, J. K., Müller-Myhsok, B., Lappalainen, T., Schumacher, J. & Hornung, V. Genetic regulatory effects modified by immune activation contribute to autoimmune disease associations. Nat Commun 8, 266 (2017).
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11. Schäfgen, J., Cremer, K., Becker, J., Kim, S., Aretz, S., Strom, T. M., Wieczorek, D. & Engels, H. De novo nonsense and frameshift variants of TCF20 in individuals with intellectual disability and postnatal overgrowth. European Journal of Human Genetics 24, 1739–1745 (2016).
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19. Hornung, V., Ellegast, J., Kim, S., Brzózka, K., Jung, A., Kato, H., Poeck, H., Akira, S., Conzelmann, K.-K., Schlee, M., Endres, S. & Hartmann, G. 5'-Triphosphate RNA is the ligand for RIG-I. Science 314, 994–997 (2006).
†Corresponding author, *Equally contributing author