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Research

1. Genomics in respiratory diseases. My early research contributions primarily focused on the identifications of the shared genetic architecture between complex diseases (e.g., allergic diseases, obesity, asthma) by using genome-wide association analysis (GWAS). These publications involved analyses of multiple population-based genetic cohorts, including the UK Biobank, China Kadoorie Biobank, Trans-National Asthma Genetic Consortium, GABRIEL consortium, and Genetic Investigation of ANthropometric Traits Consortium, and focused on outcomes such as asthma, lung function, and obesity.

 

  • Zhu Z, Lee PH, Chaffin MD, Chung, W, Loh PR, Lu Q, Christiani DC, Liang L, A genome-wide cross-trait analysis from UK Biobank highlights the shared genetic architecture of asthma and allergic diseases. Nat Genet 2018;50(6):857-864. PMCID: PMC5980765.

  • Zhu Z, Zhu X, Liu CL, Shi H, Shen S, Yang Y, Hasegawa K, Camargo CA Jr, Liang L. Shared genetics of asthma and mental health disorders: A large-scale genome-wide cross-trait analysis. Eur Respir J 2019;54(6). PMID: 31619474.

  • Zhu Z, Guo Y, Shi H, Liu CL, Panganiban RA, Chung W, O’Connor LJ, Himes BE, Gazal S, Hasegawa K, Camargo CA Jr, Qi L, Moffatt MF, Hu FB, Lu Q, Cookson WOC, Liang L. Shared genetic and experimental links between obesity-related traits and asthma subtypes in UK Biobank. J Allergy Clin Immunol 2020;145(2):537-549. PMCID: PMC7010560.

  • Zhu Z, Li J, Si J, Ma B, Shi H, Lv J, Cao W, Guo Y, Millwood IY, Walters RG, Lin K, Yang L, Chen Y, Du H, Yu B, Hasegawa K, Camargo CA Jr, Moffatt MF, Cookson WOC, Chen J, Chen Z, Li L, Yu C, Liang L. A large-scale genome-wide association analysis of lung function in the Chinese population identifies novel loci and highlights shared genetic etiology with obesity. Eur Respir J. 2021;58(4):2100199. PMCID: PMC8513692.

 

2. Transcriptomics, proteomics, and metabolomics in respiratory diseases. In addition to the contributions described above, I have investigated the association of transcriptomics, proteomics, and metabolomics with respiratory diseases. For example, by applying a Mendelian randomization approach to proteomics and GWAS data from a multicenter prospective cohort study of acute respiratory distress syndrome (ARDS) in the U.S., I have identified that plasma insulin-like growth factor binding protein 7 (IGFBP7) as a novel causal protein involved in the pathogenesis of ARDS 28-day mortality and platelet function in ARDS. In addition, by applying an unsupervised clustering approach to the nasopharyngeal airway metabolome data from a multicenter prospective cohort study in the U.S. (MARC-35), I have identified five biologically distinct and clinically meaningful metabolomics endotypes for bronchiolitis. Specifically, the endotype characterized by a high abundance of inflammatory amino acids and a low abundance of PUFAs had the highest risk of developing asthma. This body of work has emphasized the importance of evaluating transcriptomic, proteomic, and metabolomic signatures in respiratory diseases (e.g., asthma).

 

  • Dong X, Zhu Z (co-senior author), Wei Y, Ngo D, Zhang R, Du M, Huang H, Lin L, Tejera P, Su L, Chen F, Ahasic AM, Thompson BT, Meyer NJ, Christiani DC. Plasma insulin-like growth factor binding protein-7 (IGFBP-7) contributes causally to ARDS 28-day mortality: evidence from multi-stage Mendelian randomization. Chest. 2021;159(3):1007-1018. PMCID: PMC8501007.

  • Zhu Z, Camargo CA Jr, Raita Y, Fujiogi M, Liang L, Rhee EP, Woodruff PG, Hasegawa K. Metabolome subtyping of severe bronchiolitis in infancy and risk of childhood asthma. J Allergy Clin Immunol. 2022;149(1):102-112. PMCID: PMC8660920.

  • Zhu Z, Camargo CA Jr, Raita Y, Freishtat RJ, Fujiogi M, Hahn A, Mansbach JM, Spergel JM, Pérez-Losada M, Hasegawa K. Nasopharyngeal airway dual-transcriptome of infants with severe bronchiolitis and risk of childhood asthma: A multicenter prospective study. J Allergy Clin Immunol. 2022;150(4):806-816. PMCID: PMC9547815.

  • Zhu Z, Freishtat RJ, Harmon B, Hahn A, Teach SJ, Pérez-Losada M, Hasegawa K, Camargo CA Jr, Nasal airway microRNA profiling of infants with severe bronchiolitis and risk of childhood asthma: A multicenter prospective study. Eur Respir J. 2023;62(2):2300502. PMCID: PMC10578345.

 

3. Epigenomics, microbiome, and virus in respiratory diseases. In addition to the contributions described above, I have investigated the association of epigenomics, microbiome, and virus with asthma. For example, by applying EWAS approach to a multicenter prospective cohort study in the U.S. (MARC-35), we identified that blood DNA methylation signatures were associated with bronchiolitis severity at infancy and played important roles in tissues, cells, pathways, and gene expression. Additionally, in another study using the MARC-35 cohort, we have demonstrated that the abundance of Streptococcus pneumoniae at infant bronchiolitis was associated with a greater risk of developing asthma and major bacterial species contributed to both microbial functional pathways and host response that are associated with the asthma risk. This body of work has emphasized the importance of evaluating microbiome, virus and metabolome signature in severe bronchiolitis and their longitudinal association with asthma.

 

  • Zhu Z, Camargo CA Jr, Raita Y, Freishtat RJ, Fujiogi M, Hahn A, Mansbach JM, Spergel JM, Pérez-Losada M, Hasegawa K. Nasopharyngeal airway dual-transcriptome of infants with severe bronchiolitis and risk of childhood asthma: A multicenter prospective study. J Allergy Clin Immunol. 2022;150(4):806-816. PMCID: PMC9547815.

  • Zhu Z, Freishtat RJ, Harmon B, Hahn A, Teach SJ, Pérez-Losada M, Hasegawa K, Camargo CA Jr, Nasal airway microRNA profiling of infants with severe bronchiolitis and risk of childhood asthma: A multicenter prospective study. Eur Respir J. 2023;62(2):2300502. PMCID: PMC10578345.

  • Zhu Z, Li Y, Freishtat RJ, Celedón JC, Espinola JA, Harmon B, Hahn A, Camargo CA Jr, Liang L, Hasegawa K. Epigenome-wide association analysis of infant bronchiolitis severity: A multicenter prospective cohort study, Nat Commun. 2023;14(1):5495. PMCID: PMC10485022.

  • Zhu Z, Shibata R, Hoffman KL, Cormier J, Mansbach JM, Liang L, Camargo CA Jr, Hasegawa K.  Integrated nasopharyngeal airway metagenome and host genome endotyping of severe bronchiolitis in infancy and risk of childhood asthma. Eur Respir J. 2024;64(6):2401130. PMCID: PMC11685037.

 

4. Integrative multi-omics in respiratory diseases. There is growing evidence suggesting the complex interplay among different risk factors (as measured by multi-omics) of respiratory diseases. Thus, leveraging multi-omics data to disentangle the interplay becomes increasingly important. I also have expertise in advanced statistical analyses for integrating multi-omics data. Specifically, I used novel multi-omics integration methods that integrate clinical, genomics, transcriptomics, proteomics, metabolomics and microbiome data. For example, by applying an integrative microRNA and mRNA approach to a multicenter cohort of infants with severe bronchiolitis in the U.S. (MARC-35), we found a complex interplay between nasal miRNA and their mRNA targets, virus, asthma risk factors, and their longitudinal relationship with asthma development. We also demonstrated that these miRNAs play key roles in mechanisms relating to asthma (as measured by mRNA gene expression), such as innate immunity, airway remodeling, and IgE regulation. This body of work has emphasized the importance of disentangling disease mechanisms by integrating multi-omics data.

 

  • Zhu Z, Camargo CA Jr, Raita Y, Freishtat RJ, Fujiogi M, Hahn A, Mansbach JM, Spergel JM, Pérez-Losada M, Hasegawa K. Nasopharyngeal airway dual-transcriptome of infants with severe bronchiolitis and risk of childhood asthma: A multicenter prospective study. J Allergy Clin Immunol. 2022;150(4):806-816. PMID: 35483507.

  • Zhu Z, Freishtat RJ, Harmon B, Hahn A, Teach SJ, Pérez-Losada M, Hasegawa K, Camargo CA Jr, Nasal airway microRNA profiling of infants with severe bronchiolitis and risk of childhood asthma: A multicenter prospective study. Eur Respir J. 2023;62(2):2300502. PMCID: PMC10578345.

  • Zhu Z, Li Y, Freishtat RJ, Celedón JC, Espinola JA, Harmon B, Hahn A, Camargo CA Jr, Liang L, Hasegawa K, Epigenome-wide association analysis of infant bronchiolitis severity: A multicenter prospective cohort study, Nat Commun. 2023;14(1):5495. PMCID: PMC10485022.

  • Zhu Z, Shibata R, Hoffman KL, Cormier J, Mansbach JM, Liang L, Camargo CA Jr, Hasegawa K.  Integrated nasopharyngeal airway metagenome and host genome endotyping of severe bronchiolitis in infancy and risk of childhood asthma. Eur Respir J. 2024;;64(6):2401130. PMCID: PMC11685037.

 

5. Machine learning in multi-omics. I also have expertise in applying machine learning approaches to multi-omics data. Specifically, I used novel machine learning methods that analyze multi-omics data. For example, by using a polygenic risk score approach based on machine learning Bayesian framework to the large-scale genomics data of ~400,000 subjects in population-based cohort study in the U.K. (UK Biobank), we demonstrated that adults with nonallergic asthma and its genetic predisposition had a higher risk of severe COVID-19. In addition, by using a similarity network fusion approach to integrate clinical, virus, airway microbiome, transcriptome, and metabolome data of 221 infants hospitalized with RSV bronchiolitis in a multicenter prospective cohort study in the U.S. (MARC-35), we have also demonstrated that, compared to reference endotype infants, endotype B infants—who are characterized by a high proportion of IgE sensitization and RSV/rhinovirus coinfection, Streptococcus pneumoniae/Moraxella catarrhalis codominance, and high IFN-α and -γ response—had a significantly higher risk for developing asthma. This body of work has emphasized the importance of disease phenotyping/endotyping by applying machine learning approaches to multi-omics data.

 

  • Zhu Z, Hasegawa K, Ma B, Fujiogi M, Camargo CA Jr, Liang L. Association of asthma and its genetic predisposition with the risk of severe COVID-19. J Allergy Clin Immunol. 2020;146(2):327-329.e4. PMCID: PMC7423602.

  • Zhu Z, Camargo CA Jr, Raita Y, Fujiogi M, Liang L, Rhee EP, Woodruff PG, Hasegawa K. Metabolome subtyping of severe bronchiolitis in infancy and risk of childhood asthma. J Allergy Clin Immunol. 2022; 149(1):102-112. PMCID: PMC8660920.

  • Zhu Z, Li Y, Freishtat RJ, Celedón JC, Espinola JA, Harmon B, Hahn A, Camargo CA Jr, Liang L, Hasegawa K, Epigenome-wide association analysis of infant bronchiolitis severity: A multicenter prospective cohort study, Nat Commun. 2023;14(1):5495. PMCID: PMC10485022.

  • Zhu Z, Shibata R, Hoffman KL, Cormier J, Mansbach JM, Liang L, Camargo CA Jr, Hasegawa K.  Integrated nasopharyngeal airway metagenome and host genome endotyping of severe bronchiolitis in infancy and risk of childhood asthma. Eur Respir J. 2024;;64(6):2401130. PMCID: PMC11685037.

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