Characterising the genetic architecture of common elastic tissue disorders using UK Biobank

Background Elastic fibres are key extracellular matrix (ECM) components that provide elasticity to tissues throughout the body, allowing them to recover after deformation. Derangement of elastic fibres lead to cutaneous and systemic disorders that show elastic tissue pathology. To distinguish between rarer disorders of elastic tissue, and common disease, I have coined the term ‘elastopathies.’ Common elastopathies such as hiatus hernia, diverticular disease, haemorrhoids, inguinal hernia, varicose veins, female genital prolapse, umbilical hernia, aneurysmal disease, emphysema, pneumothorax, rectal prolapse, and femoral hernia, have a complex aetiology where genetic predisposition and environmental factors interplay to influence overall phenotypic expression. These elastopathies are highly prevalent and exert a significant healthcare and socioeconomic burden. However, their genetic basis remains poorly defined, with limited putative genes identified. Method To unravel the genetic architecture of the 12 elastopathies identified in the UK Biobank resource (hiatus hernia, diverticular disease, haemorrhoids, inguinal hernia, varicose veins, female genital prolapse, umbilical hernia, aneurysmal disease, emphysema, pneumothorax, rectal prolapse, and femoral hernia), genome-wide association study (GWAS) testing was performed across ~400,000 genotyped participants from the UK Biobank resource, with replication from ~410,000 participants from 23andMe, Inc. (California) for the varicose veins analysis. All 12 elastopathies were studied independently, and then combined in a final pan-elastopathy GWA study to identify the shared genetic architecture of common elastopathies in UK Biobank. A disparate analysis was performed combining all four types of hernia in a pan-hernia analysis to identify shared genetics. Genes and pathways were prioritised using a suite of bioinformatic approaches, and pharmacological targets identified using the Open Targets Platform. A genetic risk score was constructed to examine the genetic burden among participants with severe disease. For the pan-hernia analysis, multi-trait and multivariate meta-analysis approaches were deployed to uncover the shared genetic susceptibility to multiple hernia phenotypes. For the pan-elastopathy analysis, an individual patient data (IPD) meta-analysis was performed and the latent elastopathy phenotype was analysed using genomic structural equation modelling (SEM) to uncover shared genetic biology. Results Performing the largest two-stage GWAS of varicose veins in 810,625 participants, forty-nine signals at 46 susceptibility loci were discovered, including 29 previously unreported associations. Next, through (at the time) the first-ever GWA study of haemorrhoids in over 400,000 participants, 13 signals at 12 novel loci were discovered to associate with haemorrhoids. Association analysis of inguinal, femoral, umbilical, and hiatus hernia individually yielded 58 signals at 38 loci (34 new) associated with the four hernia phenotypes. When combined in a multi-trait meta-analysis, 12 biologically relevant putative loci were discovered to associate with multiple hernia phenotypes, demonstrating novel and robust evidence of shared susceptibility to hernia. Of significance, the genetic risk scoring correlated with disease severity across the varicose veins, haemorrhoids, and pan-hernia analyses, with patients undergoing surgery having a higher genetic burden than those managed non-surgically. Lastly, studying the 12 elastopathies in a pan-elastopathy IPD meta-analysis, 18 susceptibility loci were discovered to associate with the pan-elastopathy phenotype which were not discovered when the 12 elastopathies were studied individually. Moreover, employing common factor analysis to unveil the latent elastopathy phenotype, a further four loci were discovered to be integral to a shared genetic risk towards elastopathies. Collectively, over 250 independent susceptibility loci were discovered to associate with the 12 elastopathies, which were mapped to over 500 putative genes, many of which demonstrated profound evidence of a shared genetic biology, therapeutic tractability and clustered in pathways pertaining to core matrisomal components and ECM homeostasis. Conclusion Prioritised genes and pathways demonstrate significant biological plausibility, and represent promising candidates for further investigation of elastic tissue biology and potential pharmacological targeting. The genetic risk score correlated with disease across varicose veins, haemorrhoids and hernia disorders, representing an important proof-of-principle for the future use of genetic risk scoring in personalised medicine approaches to surgical disorders. Lastly, studying the 12 elastic tissue disorders together, a novel category of pathologically linked disorders defined by elastic tissue dysfunction were discovered— the elastopathies. To this end, this thesis advances the field of study around elastopathies and complex trait genetics.