Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.800111
Title: Statistical methods and analyses in autoimmune diseases
Author: Inshaw, Jamie
ISNI:       0000 0004 8507 645X
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2020
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Abstract:
Type 1 diabetes (T1D) is a common, heritable autoimmune disease, with approximately 60 chromosome regions identified that show association with disease. Cases diagnosed at < 10 years most rapidly lose the ability to endogenously produce insulin and suffer the greatest complications of the disease, including decreased life expectancy. I therefore analysed genotype data from 15, 645 cases and tested the association of each variant at a genome-wide level with age-at-diagnosis, in an attempt to reveal genes and pathways implicated in early-diagnosed T1D. Variants within the human leucocyte anti- gen (HLA) region, as expected, showed association with age-at-diagnosis, but I also found a novel T1D region on chromosome 6q22.33, which associated with both age-at-diagnosis and also disease risk if examining only cases diagnosed at < 5 years. Based on prior pancreas histology results, which showed cases diagnosed at < 7 years have a distinct immune cell infiltration signature to those diagnosed at ≥ 13 years, I then predefined specific age-at-diagnosis groups, < 7, 7-13 and ≥ 13, and restricted my analysis to examine only known T1D regions, thereby reducing the multiple testing adjustment required in genome-wide studies. Six alleles within the HLA region were more strongly associated in individuals diagnosed at < 7 years compared to ≥ 13 years, as well as six regions outside the HLA. The identified candidate causal genes indicate effects not only in the immune system but also in the islet beta cells and thymus. Finally, I performed an ImmunoChip-wide meta-analysis of 59, 974 individuals, approxi- mately twice the sample size of the previous largest T1D genetic analysis, and identified 74 chromosome regions associated with T1D, including 22 novel regions. I fine mapped each region and confirmed that prioritised variants were enriched in open chromatin re- gions in lymphoid cells. Ongoing and future research aims to go from maps, to mechanisms, to medicines.
Supervisor: Crouch, Daniel ; Todd, John Sponsor: Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.800111  DOI: Not available
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