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Discrepant effects of CREBRF on obesity and metabolic phenotypes, and signals of selection in Samoans

Russell, Emily/M (2019) Discrepant effects of CREBRF on obesity and metabolic phenotypes, and signals of selection in Samoans. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Obesity and obesity-related disorders such as type 2 diabetes have increased dramatically over the past several decades in Samoa and American Samoa and are of major public health significance for the region. In this work I explored the relationship between body mass index (BMI), type 2 diabetes, fasting glucose, and a variant, rs373863828, in CREBRF with discrepant effects on BMI and type 2 diabetes in a cohort of 4,957 Samoans and American Samoans. The minor allele of rs373863828 is common in Samoans and other Polynesians but very rare in non- Polynesians. To determine whether other variation in CREBRF is associated with BMI and type 2 diabetes in non-Polynesians, I tested for association of rare and common variants in the CREBRF region with BMI and type 2 diabetes phenotypes in a large cohort of 43,359 non-Samoans and 1,107 Samoans from the TOPMed Program. Genetic signatures of adaptation have been identified in other population isolates, so they may also be identified in Samoa, a genetically isolated population. To identify whether variants are under selective pressure in Samoa, I used a population branch statistic (PBS) analysis and nSL, a haplotype-based analysis, to identify genome-wide signals of selection. I used gene ontology enrichment to follow-up on variants identified with PBS.
In Samoans, the minor allele of the rs373863828 missense variant provides some protection from type 2 diabetes, but higher BMI is still associated with increased type 2 diabetes risk, regardless of rs373863828 genotype. I identified rare-variant sets in the CREBRF region that were associated with BMI and fasting insulin in non-Polynesians. Common variation in the CREBRF region was not associated with BMI or phenotypes related to type 2 diabetes in non-Polynesians. I identified variants under selective pressure in Samoans, which are near or in genes that are have been previously associated with BMI and the immune system. This suggests that selection may have occurred in Samoa as a response to food scarcity and/or exposure to a contagion.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Russell, Emily/Memr18@pitt.eduemr180000-0001-9151-0310
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairMinster, Ryan L.rminster@pitt.edu0000-0001-7382-6717
Committee MemberMiljkovic,
Committee MemberShaffer, John
Committee MemberWeeks, Daniel E.weeks@pitt.edu0000-0001-9410-7228
Date: 26 July 2019
Date Type: Publication
Defense Date: 3 June 2019
Approval Date: 26 July 2019
Submission Date: 22 May 2019
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 136
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Genetic Counseling
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Samoa, CREBRF, population genetics, obesity
Date Deposited: 26 Jul 2019 20:56
Last Modified: 30 Jun 2022 15:20


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