Shaffer, John R
(2008)
Genetic Epidemiology of Longitudinal Change in Bone Mineral Density in Mexican Americans: The San Antonio Family Osteoporosis Study.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Motivation: Bone mineral density (BMD), the principal determinant of bone strength and a risk factor for osteoporosis, is the net result of two processes: (i) the acquisition of peak BMD during young adulthood, and (ii) the subsequent rate of bone loss with age. While the genetics of peak BMD has been extensively studied, the specific genetic polymorphisms influencing peak BMD and the genetic contribution to bone loss are largely unknown. We investigated the extent to which genes influence 5-year change in BMD and searched for specific chromosomal regions influencing peak BMD and change in BMD in 1047 Mexican Americans from 34 large, multigenerational families. Methods: BMD measurements of the hip, spine, and forearm were collected at baseline and follow-up (3-8 years later, mean = 5.6 years) by dual-energy x-ray absoptiometry, from which annual BMD change was calculated. Pedigree-based maximum likelihood methods modeling the variance decomposition of longitudinal and cross-sectional measurements of BMD were used to estimate heritability (h²) and perform genome-wide linkage analysis (using a 7.6 cM genetic map) for BMD change and peak BMD. The effects of several environmental covariates, notably sex, age, weight, change in weight, and menopause, were simultaneously modeled.Results: We determined that change in BMD varied over time and could be categorized into two heritable (h² = 31% to 44%) phases: early adult bone loss in participants <45 years of age and later bone loss in participants >45 years of age. A quantitative trait locus (QTL) influencing early bone loss was observed on chromosome 1q (LOD = 3.6) in the cohort <45 years; no specific chromosomal regions influencing change in BMD were observed in the cohort >45 years. By comparing cross-sectional genetic analyses at baseline and follow-up, we identified QTLs on chromosomes 6q and 13q with consistent effects on peak BMD of the hip and showed that QTLs influencing peak BMD did not overlap with QTLs influencing bone loss.Public health significance: This work demonstrated the importance of genes in the etiology of osteoporosis, a growing public health problem. Understanding the genetic determinants of bone strength could lead to new biological targets for the treatment of osteoporosis, and/or the identification of persons at risk who would benefit from preventative interventions.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
23 June 2008 |
| Date Type: |
Completion |
| Defense Date: |
31 March 2008 |
| Approval Date: |
23 June 2008 |
| Submission Date: |
10 April 2008 |
| Access Restriction: |
5 year -- Restrict access to University of Pittsburgh for a period of 5 years. |
| Number of Pages: |
156 |
| 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: |
bone; bone loss; bone mineral density; heritability; linkage; osteoporosis; quantitative trait locus |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-04102008-232707/, etd-04102008-232707 |
| Date Deposited: |
10 Nov 2011 19:35 |
| Last Modified: |
30 Jun 2022 16:20 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/6970 |
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