X Xiao1,2, D Roohani1, Q Wu3,4. 1. Nevada Institute of Personalized Medicine, University of Nevada Las Vegas, 4505 Maryland Parkway, Las Vegas, NV, 89154-4009, USA. 2. Department of Environmental and Occupational Health, School of Community Health Sciences, University of Nevada Las Vegas, 4505 Maryland Parkway, Las Vegas, NV, 89154-4009, USA. 3. Nevada Institute of Personalized Medicine, University of Nevada Las Vegas, 4505 Maryland Parkway, Las Vegas, NV, 89154-4009, USA. qing.wu@unlv.edu. 4. Department of Environmental and Occupational Health, School of Community Health Sciences, University of Nevada Las Vegas, 4505 Maryland Parkway, Las Vegas, NV, 89154-4009, USA. qing.wu@unlv.edu.
Abstract
Genetic risk of low bone mineral density in women remains unclear. This study found that a large percentage of Caucasian women have a high genetic risk of osteoporosis, and genetic risk scores are significantly associated with BMD variation in a bone healthy sample of Caucasian women. INTRODUCTION: We aimed to examine the distribution of risk alleles in an independent sample and to determine if such genetic components are associated with bone mineral density (BMD) variation in the sample. METHODS: Existing genotype data of 1205 women in the cross-sectional Genomic Wide Scans for Female Osteoporosis Gene Study (GWSFO) were analyzed. Multi-loci genetic risk scores (GRSs) based on 62 BMD-associated single nucleotide polymorphisms (SNPs) were calculated. Regression analysis was employed to assess the association between GRSs and BMD. To examine the effect of SNPs clustered within key pathways associated with the development of osteoporosis, subtype weighted GRS specific to WNT signaling (6 SNPs), RANK-RANKL-OPG (3 SNPs), and mesenchymal stem differentiation (3 SNPs) were generated for analysis. RESULTS: The unweighted GRS ranged from 48 to 80. One third of the women carried 66% risk alleles. After adjusting for age, height, and body weight, each unit increase of weighted GRS was associated with a decrease in BMD of 0.097 at femur (p < 0.0001) and 0.110 (p < 0.0001) at lumbar spine. The weighted GRS accounted for only 3.17-4.52% of BMD variance. The WNT signaling pathway GRS (6 SNPs) and the RANK-RANKL-OPG signaling pathway GRS (3 SNPs) both were significantly associated with decreased BMD at femur neck (p = 0.0004 and p = 0.0063, respectively) and lumbar spine (p < 0.0001 and p = 0.0001, respectively), while the mesenchymal stem cell differentiation pathway (3 SNPs) GRSs were associated only with the lumbar spine BMD (p = 0.045). CONCLUSIONS: A substantially large percentage of healthy Caucasian women have a high genetic risk of osteoporosis. Weighted GRS was significantly associated with decreased BMD. The contribution of subtype GRS to the BMD variation differs by specific biological pathway and skeletal regions.
Genetic risk of low bone mineral density in women remains unclear. This study found that a large percentage of Caucasian women have a high genetic risk of osteoporosis, and genetic risk scores are significantly associated with BMD variation in a bone healthy sample of Caucasian women. INTRODUCTION: We aimed to examine the distribution of risk alleles in an independent sample and to determine if such genetic components are associated with bone mineral density (BMD) variation in the sample. METHODS: Existing genotype data of 1205 women in the cross-sectional Genomic Wide Scans for Female Osteoporosis Gene Study (GWSFO) were analyzed. Multi-loci genetic risk scores (GRSs) based on 62 BMD-associated single nucleotide polymorphisms (SNPs) were calculated. Regression analysis was employed to assess the association between GRSs and BMD. To examine the effect of SNPs clustered within key pathways associated with the development of osteoporosis, subtype weighted GRS specific to WNT signaling (6 SNPs), RANK-RANKL-OPG (3 SNPs), and mesenchymal stem differentiation (3 SNPs) were generated for analysis. RESULTS: The unweighted GRS ranged from 48 to 80. One third of the women carried 66% risk alleles. After adjusting for age, height, and body weight, each unit increase of weighted GRS was associated with a decrease in BMD of 0.097 at femur (p < 0.0001) and 0.110 (p < 0.0001) at lumbar spine. The weighted GRS accounted for only 3.17-4.52% of BMD variance. The WNT signaling pathway GRS (6 SNPs) and the RANK-RANKL-OPG signaling pathway GRS (3 SNPs) both were significantly associated with decreased BMD at femur neck (p = 0.0004 and p = 0.0063, respectively) and lumbar spine (p < 0.0001 and p = 0.0001, respectively), while the mesenchymal stem cell differentiation pathway (3 SNPs) GRSs were associated only with the lumbar spine BMD (p = 0.045). CONCLUSIONS: A substantially large percentage of healthy Caucasian women have a high genetic risk of osteoporosis. Weighted GRS was significantly associated with decreased BMD. The contribution of subtype GRS to the BMD variation differs by specific biological pathway and skeletal regions.
Entities:
Keywords:
Bone mineral density; Caucasian women; Genetic risk score; Osteoporosis
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