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Genetic Associations Between GDF5 and Physical Disability Phenotypes: A PHEWAS Approach

Riazzi, Nathan (2022) Genetic Associations Between GDF5 and Physical Disability Phenotypes: A PHEWAS Approach. Master's Thesis, University of Pittsburgh. (Unpublished)

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Background: Declining physical function typically results in increased disabilities, medical institutionalization, health-care costs, and premature mortality. Along with this, low physical function leads to lower quality of life and dependencies. Prior research has identified potential risk factors for physical disability such as lifestyle factors and chronic health risks. However, interventions targeting these risk factors are minimal. This makes it imperative to identify genetic risk factors, which are largely unknown. GDF5 is a novel gene that has been a target in recent genetic studies that identify associations with physical disability.
Methods: PHEWAS technologies are used to identify associations between genetic variants and phenotypes of interest (gait speed, grip strength, FEV1, SPPB, Chair rise, SAVE, and a composite mobility disability score). We have employed PHEWAS analyses accompanied by mixed general linear models that include a kinship matrix to account for the familial relatedness of our sample population. We also controlled for age, sex, visit site, and height. To capture GDF5 and other regulatory genes, we determined gene boundaries using Ensembl genome browser
Results: There were 4440 participants (55% female and 45% male) involved in this analysis, using the Long Life Family Study which is a familial cohort of exceptional longevity. Descriptive results show that the mean age was 69.8. Association analyses showed 52 nominally significant SNPs across all age groups and phenotypes, and 82 nominally significant SNPs across all phenotypes in those aged 60+. We also experienced pleiotropic properties in certain SNPs. For example, RS11814750 is nominally significant with 9 phenotypes that are predictors of physical disability. Results also revealed a mediation effect with height that brought out significant SNPs that were not associated with phenotypes before height adjustment.
Conclusion: Understanding the genetic component to physical decline and function is necessary to improve quality of life and overall mobility. Results of this PHEWAS analysis will identify candidate SNPs that affect multiple phenotypes related to the physical disability and will also provide the framework for novel therapeutic and prevention measures, which will resolve the public health crisis of limited therapeutics for physical disability.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Riazzi, Nathanncr22@pitt.eduncr22
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairSantanasto, Adamajs51@pitt.eduajs51
Committee MemberMinster, Ryanrminster@pitt.edurminster
Committee MemberZmuda, Joezmudaj@edc.pitt.eduzmudaj
Date: 30 August 2022
Date Type: Publication
Defense Date: 21 July 2022
Approval Date: 30 August 2022
Submission Date: 12 August 2022
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 57
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Epidemiology
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: PHEWAS GDF5 Physical Disability
Date Deposited: 30 Aug 2022 12:54
Last Modified: 30 Aug 2022 12:54


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