The genetics of osteoporosis

Duncan, Emma (2002). The genetics of osteoporosis. PhD thesis The Open University.



This thesis presents epidemiological and gene mapping studies of the genetics of osteoporosis and low bone mineral density (BMD). BMD is a highly heritable trait. However the genes that underlie the population variance in BMD remain unknown.

Genetic epidemiological studies of families collected for gene mapping investigations demonstrated significantly low BMD in siblings and relatives of probands with osteoporosis. A sibling recurrence risk ratio (Xs) for low BMD was established, with Xs of 6.26 at lumbar spine (LS) and 5.24 at femoral neck (FN), and heritability of BMD estimated at 60% for LS and 48% for FN. There was also evidence of both site- and gender-specific genetic effects.

A large candidate gene linkage study demonstrated linkage of BMD with several loci, notably Parathyroid Hormone Receptor Type 1 (PTHRl), type 1 Collagen alpha-1 (COLlAl), type 2 Collagen alpha-1/Vitamin D Receptor, Interleukins 1,4 and 6, Epidermal Growth Factor, RANKL and Estrogen Receptor-alpha.

Mutation screening of PTHRl exons and promoter regions revealed both previously described and new polymorphisms. Association of BMD at LS with a polymorphism present in exon M7 of PTHRl was demonstrated in both population-based and within family association studies.

A within-family association study of a polymorphism in the first intron of COL1A1 found no evidence of association with BMD. However, when only maternal transmissions were considered, there was evidence of association with BMD at FN, suggesting the possibility of imprinting of this gene.

Further genetic studies of PTHR1 and other genes identified as contributing to the population variance of BMD will help clarify their roles in the determination of BMD and the development of osteoporosis.

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