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Psychiatric and Pain Risk Genes that May Worsen Quality of Life in Chronic Pancreatitis Patients

Dunbar, Ellyn (2022) Psychiatric and Pain Risk Genes that May Worsen Quality of Life in Chronic Pancreatitis Patients. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Pancreatitis, a fibro-inflammatory disease, can result in debilitating abdominal pain. Pancreatitis pain is difficult to treat even with surgery and opioids. The pain caused by pancreatitis varies in severity and frequency even within patients with similar physical disease states. The purpose of the collection of papers in this dissertation is to identify genetic variation between pancreatitis patients within different patterns of pain in hopes that these results can be used to guide future precision medicine treatments of pancreatitis pain.
At most 1,357 patients with chronic and/or recurrent acute pancreatitis from the North American Pancreatitis Study II of European Ancestry were studied across all three aims. Aim 1 used a GWAS to identify that some genetic risk loci (n=15, p<1e-04) for constant-severe pain in pancreatitis were in genes (n=13, p-value of overlap 0.51) that have previously been identified as associated with unipolar depression from the GWAS Catalog (n=1380). For example, CTNND2 and BAIAP2 had loci associated with constant-severe pain. Similarly, using a candidate gene study Aim 2 found loci associated with constant, constant-severe, and severe pain located within genetic risk genes for anxiety and PTSD, such as CTNND2, HTR2A, DRD3, and BDNF. A literature review was used to compile the list of 28 anxiety/PTSD candidate genes used in Aim 2. Of those genes, 13 contained 24 lead SNPs (p<0.002) associated with pancreatitis pain. Aim 3 pulled the focus back to genome-wide associations and post-genome-wide association study methods, such as a transcriptome-wide association study (p<2.8e-06, suggestive p<1e-04) and colocalization, to identify associations with constant, constant-severe, and severe pain in patients with chronic and/or recurrent acute pancreatitis in a hypothesis generating manor. This final aim found that differential expression of CTRC in pancreas tissue was associated with the constant pain phenotype. Additionally, differential expression of HSF2 in skin was associated with the constant-severe phenotype. Finally, differential expression of DOK6 in nerves was associated with the severe pain phenotype.
These results are new in the field, and necessary for future studies into precision treatments for patients with pancreatitis pain that could replace ineffective pain treatments and increase patients’ physical and mental quality of life.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Dunbar, Ellyneld85@pitt.edueld850000-0001-9214-6960
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairWhitcomb, David C.whitcomb@pitt.eduwhitcomb
Committee MemberWeeks, Daniel E.weeks@pitt.eduweeks
Committee MemberFinegold, Daviddnf@pitt.edudnf
Committee MemberShaffer, John R.john.r.shaffer@pitt.edujohn.r.shaffer
Date: 30 August 2022
Date Type: Publication
Defense Date: 13 July 2022
Approval Date: 30 August 2022
Submission Date: 10 August 2022
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 191
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Human Genetics
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: human genetics, statistical genetics, pancreas
Date Deposited: 30 Aug 2022 13:45
Last Modified: 30 Aug 2023 05:15


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