An Atlas of Genetic Variation Linking Pathogen-Induced Cellular Traits to Human Disease.

Abstract

Pathogens have been a strong driving force for natural selection. Therefore, understanding how human genetic differences impact infection-related cellular traits can mechanistically link genetic variation to disease susceptibility. Here we report the Hi-HOST Phenome Project (H2P2): a catalog of cellular genome-wide association studies (GWAS) comprising 79 infection-related phenotypes in response to 8 pathogens in 528 lymphoblastoid cell lines. Seventeen loci surpass genome-wide significance for infection-associated phenotypes ranging from pathogen replication to cytokine production. We combined H2P2 with clinical association data from patients to identify a SNP near CXCL10 as a risk factor for inflammatory bowel disease. A SNP in the transcriptional repressor ZBTB20 demonstrated pleiotropy, likely through suppression of multiple target genes, and was associated with viral hepatitis. These data are available on a web portal to facilitate interpreting human genome variation through the lens of cell biology and should serve as a rich resource for the research community.

Department

Description

Provenance

Citation

Published Version (Please cite this version)

10.1016/j.chom.2018.07.007

Publication Info

Wang, Liuyang, Kelly J Pittman, Jeffrey R Barker, Raul E Salinas, Ian B Stanaway, Graham D Williams, Robert J Carroll, Tom Balmat, et al. (2018). An Atlas of Genetic Variation Linking Pathogen-Induced Cellular Traits to Human Disease. Cell host & microbe, 24(2). pp. 308–323.e6. 10.1016/j.chom.2018.07.007 Retrieved from https://hdl.handle.net/10161/24734.

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Scholars@Duke

Wang

Liuyang Wang

Assistant Research Professor of Molecular Genetics and Microbiology

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.

Salinas

Raul Salinas

Research Associate, Senior
Horner

Stacy M. Horner

Associate Professor in Integrative Immunobiology

Studying the RNA biology, cell biology, and immunology of RNA virus infection

Our lab studies the molecular mechanisms that regulate RNA virus-host interactions. We focus primarily on viruses in the Flaviviridae family of viruses, including dengue virus (DENV), Zika virus (ZIKV), and hepatitis C virus (HCV). Our research is focused on defining (1) how these viruses replicate, (2) the mechanisms that regulate antiviral innate immunity to these viruses, and (3) RNA regulatory controls to both of these processes. Our lab has pioneered approaches to how the RNA modification m6A regulates viral infection, antiviral innate immunity and the host response to virus infection. Our long-term goal is to discover the necessary mechanistic and functional information to guide future development of new strategies for virus treatment and prevention.

Lab Website

Mark DeLong

Adjunct Instructor in the Duke Initiative for Science & Society
Valdivia

Raphael H. Valdivia

Nanaline H. Duke Distinguished Professor of Molecular Genetics and Microbiology

My laboratory is interested in microbes that influence human health, both in the context of host-pathogen and host-commensal interactions. For many pathogens, and certainly for most commensal microbes, we have an incomplete molecular understanding of how host and microbial factors contribute to health and disease. My research group focuses on two experimental systems:

Chlamydia trachomatis infections are responsible for the bulk of sexually transmitted bacterial diseases and are the leading cause of infectious blindness (trachoma) in the world. Chlamydia  resides within a membrane bound compartment (“inclusion”). From this location, the pathogen manipulates the cytoskeleton, inhibits lysosomal recognition of the inclusion, activates signaling pathways, re-routes lipid transport, and prevents the onset of programmed cell death. Our laboratory focuses on identifying and characterizing the bacterial factors that are secreted into the host cell cytoplasm to manipulate eukaryotic cellular functions. We use a combination of cell biology, biochemistry, genetics, genomics, proteomics and molecular biology to determining the function of virulence factors that reveal novel facets of the host-pathogen interaction. Our goal is to understand how these obligate intracellular bacterial pathogens manipulate host cellular functions to replicate, disseminate and cause disease, and in the process develop strategies to ameliorate the damage caused by these infections to the female reproductive organs.

Akkermansia muciniphila is prevalent member of the gut microbiota that proliferates in the mucus layers of our lower gastrointestinal tract and contribute to nutrient homeostasis and human immunological health. My research group developed genetic tools to characterize these microbes to define the mechanisms used to colonize the human gut and identify the molecular and cellular pathways that underscore Akkermansia's impact on immune homeostasis.  In the process, we seek to engineer strains of Akkermansia that enhance their probiotic potential.

Ko

Dennis Ko

Associate Professor in Molecular Genetics and Microbiology

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.


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