Author's School

Graduate School of Arts & Sciences

Author's Department/Program

Biology and Biomedical Sciences: Human and Statistical Genetics


English (en)

Date of Award

January 2011

Degree Type


Degree Name

Doctor of Philosophy (PhD)

Chair and Committee

Anne Bowcock


Psoriasis: PS) is a common incurable inflammatory skin disease affecting 2-3% of the European population. ~10-30% of patients develop psoriatic arthritis: PsA). Genetic variation in the major histocompatibility complex: MHC) increases risk of developing PS. However, only ~10% of individuals with this risk factor develop PS, indicating that other genetic effects and environmental triggers are important. In order to identify novel susceptibility genes of PS and PsA, I performed the first large scale genome wide association scan for psoriasis susceptibility loci using 233 cases and 519 controls. It revealed that genes of the immune system and of the barrier are associated with psoriasis. The MHC: psoriasis susceptibility 1 or PSORS1) conferred the strongest risk factor for PS and PsA. The study also confirmed recently identified associations with interleukin-23 receptor and interleukin-12B in both PS and PsA. Novel loci with modest effect were also identified, including a region on chromosome 4q27 that contains genes for interleukin 2 and interleukin 21 that has been implicated in other autoimmune diseases, and seven additional regions that included chromosome 13q13 and 15q21. A follow-up study, aimed to identify potential functional SNPs in the PSORS1 region, implicated an allele-specific repressor role of SNP rs10456057 via binding to nuclear transcriptional factors. Further study with additional PSORS1 SNPs identified "enhancer" activity of the risk allele of SNP rs13191343 in differentiating keratinocytes, and the presence of the PSORS1 risk allele is correlated with CDSN: corneodesmosin) expression, which would affect skin barrier formation. Finally, this thesis also describes the first genome-wide study of altered CpG methylation in psoriatic skin. The study determined the methylation levels at 27,578 CpG sites in skin samples from individuals with psoriasis: 12 involved, 8 uninvolved) and 10 unaffected individuals. Involved skin differed from normal skin at 1,108 CpG sites at adjusted p-value < 0.05. Twelve of those CpG sites mapped to the epidermal differentiation complex close to genes that are highly up-regulated in psoriasis. Hierarchical clustering of 50 of the top differentially methylated sites accurately separated all psoriatic skin samples: involved and uninvolved) from normal skin. Methylation at 12 CpG sites was significantly correlated with expression levels of a nearby gene. Taken together, the thesis reveals that the genetic and epigenetic risk factors of psoriasis lead to alterations in genes of skin barrier and immune system which act together to trigger the pathogenesis of the disease.



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