CPAG: software for leveraging pleiotropy in GWAS to reveal similarity between human traits links plasma fatty acids and intestinal inflammation.

Leveraging bioinformatics and big data to understand the intricacies of human diseases.

My overall research goals are centered on unraveling the molecular mechanism underpinning human disease susceptibility and harnessing these findings to innovative diagnostic and therapeutic strategies. I have adopted a multidisciplinary approach that integrates genomics, transcriptomics, and computational biology. Leveraging high-throughput cellular screening and genome-wide association study (GWAS), we have successfully identified hundreds of genomic loci associated with 8 different pathogens (Wang et al. 2018). Utilizing single-cell RNA-seq, we developed scHi-HOST to rapidly identify host genes associated with the influenza virus (Schott and Wang, et al. 2022). I also have developed several novel statistical tools, CPAG and iCPAGdb, that estimate genetic associations among human diseases and traits (Wang et al. 2015, 2021). Combining experimental and computational approaches, I expect to gain a deeper understanding of the genetic architecture of human susceptibility to infection and inflammatory disorders.

We seek to understand how the intestinal microbiome contributes to vertebrate physiology and disease. To that end, we leverage complementary zebrafish and mouse models to study the integrative physiology of host-microbiome interactions. This work has identified novel and conserved mechanisms by which intestinal bacteria regulate dietary fat metabolism and systemic innate immunity. We also apply genomic approaches in these animal models to understand the transcriptional regulatory pathways utilized by the intestinal epithelium to mediate host responses to the microbiome. Using this approach, we have identified mechanisms of transcriptional and chromatin regulation that have been conserved during vertebrate evolution and also contribute to modern human diseases such as the inflammatory bowel diseases, obesity, and diabetes. To further advance our understanding of obesity pathophysiology, we developed the zebrafish as a model system for studying adipose tissues and identifying new environmental and genetic regulators of adiposity. We are also engaged in translational research in humans and animal models to define microbial and metabolic determinants of obesity and efficacy of weight loss intervention. Grounded in comparative and integrative physiology, our research program has been effective in discovering ancient mechanisms of host-microbiome interaction that are conserved across animal taxa and contribute to the etiology of modern human diseases. These insights are advancing our understanding of host-microbiome relationships in vertebrate physiology and identifying novel therapeutic targets for human diseases ranging from inflammatory bowel disease to obesity to neurological disorders.

Tuberculosis: Mycobacterial Pathogenesis and Host Susceptibility

Tuberculosis kills 1.5 million people annually. Our laboratory aims to understand the intricate interplay between mycobacteria and their hosts using a combination of model organism genetics, human genetics, pharmacology and high-resolution microscopy. By identifying key pathways utilized by the infecting bacteria and the host innate immune system, we hope to discover new therapeutic targets and interventions to combat this enduringly destructive disease.

Using a Mycobacterium/zebrafish model, we have identified new host susceptibility loci for tuberculosis. Zebrafish are natural hosts to Mycobacterium marinum, the closest relative of the Mycobacterium tuberculosis complex. Because zebrafish embryos and larvae are optically transparent, we are able to visualize the complex details of mycobacterial pathogenesis in whole, live animals. The facile genetics of the zebrafish allow us to map and positionally clone affected host susceptibility genes. In addition, zebrafish larvae are remarkably permeable to small molecules, providing a platform for whole-animal pharmacological manipulation of specific host immune responses.

We have identified novel pathways that modulate susceptibility to tuberculosis. We have shown that genes identified in the zebrafish model are also important in human tuberculosis. We find robust associations of human variants in a specific eicosanoid pathway with susceptibility to both tuberculosis and leprosy.

We have active collaborations in both Vietnam and Guatemala. In Guatemala, we are working with the Clínica Familiar Luis Angel García and the Asociación de Salud Integral to support projects involving HIV-infected patients and to understand the dynamics of TB transmission in Central America.

Using Pathogens to Decipher Genetic Variation Connecting Cell Biology and Disease Susceptibility
Despite improvements in public health, advancements in vaccines, and the development of many classes of antibiotics, infectious disease is still responsible for over a quarter of all deaths worldwide. However, even for the most devastating of pandemics, individuals demonstrate a large variability in the severity of infection. The long-term goal of the lab is to understand the genetic basis for differences in susceptibility to infection and related inflammatory disorders. We approach this question through a combination of experimental and computational approaches that combine high-throughput cell biology with quantitative human genetics. The identified genetic differences serve as the starting point for exploring new cell biology and human disease susceptibility genes.