CANDIDATE GENE ASSOCIATION STUDY OF BASELINE AND LONGITUDINALBONE-QUALITY TRAITS IN A HEALTHY OLDER POPULATION

摘要

Motivation: Areal bone mineral density (BMD) is one of the major risk factors for osteoporosis, a public health concern in the US and other countries. The goal of our study was to identify genes that influenced areal BMD in a population of older, originally healthy, African American and Caucasian American individuals.Methods: We used three genetic association methods (single SNP-single trait, single SNP-multiple trait, multiple SNP-single trait) to test for association between measures of BMD at three time points (2 years apart) and genotype data on 1439 single nucleotide polymorphisms (SNPs) in 138 candidate genes. We first developed a model to determine the genetic (SNP) coverage of our candidate genes, and then we assessed possible population within our populations, two factors that influence the power of association studies. We also investigated the effect of covariates on BMD traits using both cross-sectional as well as longitudinal methods, and used the BMD residuals from these analyses in our association studies.Results: The SNP coverage of our candidate genes was reasonable, 52.99% compared to the theroetical HAPMAP coverage of 55.8%. We also classified our Caucasian American and African Americans based on genetic ancestry and controlled for subtle substructure. We detected several associations between candidate genes and BMD traits in all the four groups, but the most significant and consistent result was obtained in Caucasian American males. Five SNPs in the GNRHR locus were significantly associated with hip BMD trait using both the single SNP association approaches, as well as the pathway based analysis. These results need to be followed up in additional populations.Public Health Significance: As the world population ages, the cost, rate of mortality and morbidity of osteoporosis is also increasing. Identification of genes that influence risk of developing osteoporosis may help identify people at risk, as well as facilitate development of drugs and other measures to mitigate the effects of this disease.