By Kasper Fischer-Rasmussen
Principal supervisor: Klaus Bønnelykke
Principal co-supervisor: Anders Gorm Pedersen
Co-supervisor: Anders Ulrik Eliasen
Chairperson: Allan René Linneberg, MD, PhD, Professor (Chair), Institute of Clinical Medicine, University of Copenhagen, Denmark
Opponent: Qingling Duan, PhD, Associate Professor at the Department of Biomedical and, Molecular Sciences & School of Computing, Queen’s University, Canada
Opponent: Michael H. Cho, MD, Assistant Professor at Channing Division of Network, Medicine, and Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
Summary
Wheezing in preschool children presents a significant risk of progression to childhood asthma and understanding heterogeneity among these symptoms is crucial for optimal prevention and treatment strategies. Genetics is thought to play a detrimental role in asthma progression and this thesis presents three research projects that aim to elucidate the underlying mechanisms of wheeze subtypes in order to understand the genetic heterogeneity of preschool wheeze. The first study is a meta-analysis across 22 birth cohorts defining wheeze trajectories based on prior knowledge of remission patterns. Secondly, hospitalization records of asthma and bronchitis are used to define severe wheeze across 5 nordic biobanks comprising the largest GWAS of preschool wheeze to date. Lastly, prescription records are utilized to define trajectories of medication consumption using latent class analysis and subsequent genetic characterization to elucidate putative endotypes.
In paper I, we compiled GWAS results from the EAGLE and GABRIEL consortia, creating the largest GWAS of temporal wheezing phenotypes in preschool children, involving over 18,000 children from 22 studies. This study investigated phenotypes including early-onset wheeze (EOW), transient-early wheeze (TEW), persistent wheeze (PW), and current asthma (CA), with the aim of elucidating genetic differences and similarities between different symptom trajectories. We integrate publicly available GWAS of asthma and asthma-related comorbidities to characterize the genetic overlap preschool wheeze subtypes. We conclude that persistent wheeze is genetically similar with both childhood- and adult-onset asthma, atopic traits and low lung function. Transient-early wheeze displayed little to no association with asthma and atopy, but a significant overlap with low lung function.
In paper II, we disregard the timing of wheeze symptoms and include nearly 20,000 preschoolers with severe wheeze defined by at least one hospitalization with asthma, bronchitis or bronchiolitis before the age of seven. We apply a multitude of statistical analyses and GWAS-specific methods to unveil molecular mechanisms involved in risk of severe wheeze. We identified eight novel loci involved in airway inflammation, lung function and growth–five of which replicated in an independent cohort. We identify significant genetic correlations with BMI, height and c-reactive protein, SNP-groups with distinct associations to atopic traits and lung function, clinical fingerprint and transcriptomic signatures of individuals with high genetic risk severe wheeze. This comprehensive approach aims to improve our detailed understanding of the molecular biology of preschool wheeze and to identify loci with distinct association patterns, representing genetic driving forces behind potential endotypes.
In paper III, we employed latent class analysis to identify trajectories in use of inhaled corticosteroids leveraging the Danish National Prescription Registry coupled with the iPSYCH cohort. We subsequently characterize the identified trajectories by their association patterns with perinatal and genetic risk factors. Lastly, we carry out statistical testing to evaluate if risk factors have distinct impacts on the trajectories and our results suggest the presence endotypes of wheeze. We identified an array of distinctly associated risk factors like c-section, smoking during pregnancy, premature birth, IL-13, FUT2 and HLA-DQA1 and genetic risk for asthma, allergy and eosinophils and a number of putatively distinct associations. These results implicated that the proposed endotypes differ in genetic influence, T2-high response and infection propensity.
