| Osteoporosis is a major public health problem, especially in the elderly. Genetic factors play an important role in susceptibility to osteoporosis. Decades of extensive efforts have been made to search for genetic variants underlying osteoporosis. However, as a classic complex disease, the pattern of inheritance is complex. The variants identified by previous genetic studies could explain, in combination, only a very small fraction of the osteoporosis risk. Many additional genetic variants influencing osteoporosis and its related traits have to be discovered. In this dissertation, taking advantage of recent technological advances in human genetics, such as genome-wide association analyses, we performed a comprehensive genetic study to identify novel susceptibility genes for osteoporosis and its related traits.Bone mineral density (BMD) measured at femoral neck is the most important risk phenotype for osteoporosis and has been used as a reference standard for describing osteoporosis. We first perfromed a genome-wide association analysis for femoral neck BMD in a discovery sample comprising 983 unrelated Caucasian subjects. We then tested those top significant SNPs for replication in a family-based sample of 2,557 Caucasian subjects. Combining results from these two samples, we identified two susceptibility genes, PTH and IL21R, which may influence femoral neck BMD variation. PTH and IL21R both have potential biological functions important to bone metabolism. Our findings provide some new clues to the understanding of the genetic architecture of osteoporosis.The clinical consequence of osteoporosis is having fragility fractures. Of these, hip fractures are regarded as the most severe osteoporotic fractures due to the high morbidity and mortality. Using the Affymetrix 500K array set, we first performed a genome-wide association study in 700 elderly Chinese Han subjects (350 with hip fractures and 350 healthy matched controls). A follow-up replication study was conducted to validate our major results in an independent Chinese sample containing 390 cases with hip fractures and 516 controls. We identified that, a gene ALDH7A1 was strongly associated with the risk of hip fractures. We further examined this gene’s relevance to hip BMD in a total of 11,848 subjects from Chinese, Caucasian and African populations. This gene was consistently associated with hip BMD even across ethnic boundaries, in both Chinese and Caucasians, but not in African. Our findings could be used to identify quantifiable measures for early prevention and intervention before the adverse clinical outcome, fractures, actually occurs.In light of estrogen’s functional role in bone homeostasis, genes related to estrogen are key candidate genes for hip fractures. We aimed to investigate whether the genetic polymorphisms in the estrogen receptor genes, ESR1 and ESR2, affect the onset of hip fractures in an elderly Chinese sample. We first found that, several novel SNPs in ESR1 and ESR2 genes were significantly associated with hip fractures in Chinese. Our findings have important implications for understanding the pathology of osteoporotic fractures.Recently, population genetics analysis has suggested a functional role for common variants in mitochondrial DNA (mtDNA). Besides analyzing human nuclear genome, we extended our study to mitochondrial genome. For the first time, we conducted an association analysis between mitochondrial SNP (mtSNP) and BMD in 2,286 unrelated Caucasian subjects, and further explored interactions between mitochondrial genes and nuclear genes. We first discovered that, mitochondrial gene ND2 was associated with hip BMD. We also found the significant interaction effect between ND2 gene and nuclear gene ATP5J. Our findings provide a novel insight into the pathogenesis of osteoporosis.Osteoporosis is much more common in females than males. Age at menarche is an important anthropological variable that has major implication for a woman’s health later in life. Late menarche increases the risk of osteoporosis. Using the most advanced technology Genome-wide Human SNP Array 6.0, we performed a genome-wide association study in a total of 4,320 Caucasian females. We first found the significant association between PTPRG gene and age at menarhce. Meanwhile, we validated the association for a previously reported gene LIN28B with age at menarche. From a clinical point of view, understanding the potential factors responsible for the age at menarche may shed light on the pathophysiology of osteoporosis.In summary, this work represents our best effort to perform a comprehensive genetic study, aiming to identify susceptibility genes for osteoporosis and its related traits. A series of valuable results have been gained. |
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