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Defining the key biological and genetic mechanisms involved in psoriasis
[Thesis]. Manchester, UK: The University of Manchester; 2018.
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Abstract
Background: Psoriasis is a common, complex autoimmune disorder of the skin. The genetic basis of psoriasis has been partially characterised by genome wide association studies (GWAS) that have identified a number of underlying genetic signals. GWAS have also begun to explain the genetics underlying the dichotomy in age-of-onset of psoriasis, where a distinct subset of patients develops psoriasis later in life (late-onset psoriasis; LOP). However, in most loci the disease causal variant or target gene remains unknown. Aims: The broad aim of this study was to improve our understanding of the genetics of psoriasis. Firstly, the study aimed to define genetic variants underpinning LOP. Secondly, the study aimed to use functional genomic techniques to determine the mechanism by which known non-coding signals affect gene function in psoriasis-associated loci, focusing on confirmed psoriasis signals. Methods: To further define the genetic signals underpinning LOP, a GWAS was carried out comparing a cohort of patients with LOP against psoriasis-free controls. Two approaches were then taken to determine the function of known risk variants for psoriasis. Firstly, DNA-DNA and DNA-protein interactions were examined in two loci of interest in a hypothesis-driven manner. Secondly, a more hypothesis-free approach used capture Hi-C (CHi-C) to determine likely gene targets across all known psoriasis risk loci. Results: The GWAS for LOP confirmed association with known psoriasis signals, but did not validate a previously identified LOP signal at IL1R1. Twelve novel signals reached study-wide, but not genome-wide significance. The locus-specific functional work provided evidence for gene targets in the two loci studied, notably KLF4 in the 9q31 locus. The CHi-C study identified interactions between psoriasis-associated loci and promoters of approximately 1000 genes and non-coding RNAs, providing compelling targets for further study. Summary: This work has broadened our view of the genetic mechanisms underlying psoriasis. Whilst the LOP GWAS did not validate the IL1R1 locus, the novel suggestive signals prompt further analysis to confirm an association with age-of-onset. The functional work uncovered novel mechanisms in psoriasis risk loci; this evidence can be taken forward for further functional and clinical applications.