GWAS for Genetic Determinants of Bone Fragility

Osteoporotic fractures are largely due to an increased propensity to fall with aging and a reduction in bone strength.

Although skeletal architecture contributes to fracture risk, bone mineral density (BMD) is the most important determinant of bone

strength and fracture risk. Between 60 and 80% of the variance of BMD of adult Caucasian women is due to heritable factors.

Final BMD is a function of peak bone mass attained during young adulthood and the subsequent rate of bone loss, which occurs

as a result of both post-menopausal estrogen loss and aging. The evidence for a genetic contribution to rate of loss in BMD is substantially

weaker than that for peak BMD. Therefore, we have focused our sample collection on the recruitment of premenopausal women, in whom we have

sought to identify the genes influencing peak BMD at the spine and hip, the two major skeletal sites of osteoporotic fracture.

The primary goal of this study is to identify genes that affect peak BMD in premenopausal women. Identification of these genes may:

1) lead to molecular tests that predict risk of osteoporosis and allow institution of early preventive measures; 2) provide insight

into basic bone cell biology and other factors that affect peak BMD; and 3) provide molecular targets for therapeutic agents to increase BMD.]]>
The sample consists of European-American premenopausal sister pairs from Indiana, at least 20 years of age. The subjects were

recruited without regard to bone density or other clinical phenotype, and therefore represent an ideal cohort in which to

study genetic influences on normal variation in peak BMD. The exclusion criteria were limited to irregular menses or a history

of pregnancy or lactation within three months prior to enrollment, a history of chronic disease, current medications known to affect

bone mass or metabolism, or inability to have BMD measured due to obesity.]]>
Genetic studies of bone density at Indiana have been ongoing since 1988, beginning with studies in twin pairs. This has expanded

over time to include sibling pair linkage and association studies of both men and women, and both European-American and African-American

subjects. Peak bone mineral density as measured premenopausally in women and before age 60 in men is the primary quantitative

phenotype of interest, specifically at the femoral neck and lumbar spine.]]>