Abstract
Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR < 0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity.
Highlights
Low bone mineral density (BMD) is an important human phenotype predisposing for bone fractures [1]
Several lines of evidence suggest an overlap between BMD/osteoporosis and several traits related to metabolism and cardiovascular disease (CVD): -presence of osteoporosis is associated with a ~4-fold increase in risk for an acute cardiovascular event [3].—BMD loss is associated with increased mortality from coronary heart disease and pulmonary diseases [4]- an inverse relationship is found between high-density lipoprotein (HDL) cholesterol and BMD [5,6,7,8,9]
Conditional Q-Q plots for femoral neck (FN) BMD conditioned on nominal p-values of association with type 1 diabetes (T1D), type 2 diabetes (T2D), systolic blood pressure (SBP), diastolic blood pressure (DBP), high density lipoprotein (HDL), low density lipoprotein (LDL), TG and waist hip ratio (WHR) showed enrichment across different levels of significance (Fig 1 and S5 Fig)
Summary
Low bone mineral density (BMD) is an important human phenotype predisposing for bone fractures [1]. Primary and secondary osteoporosis, (defined as BMD less than 2.5 SD of young controls) occur frequently in all populations and lead to high risk for fractures and lasting functional impairment, resulting in long term personal suffering and high social costs [2]. The relationship between low-density lipoprotein (LDL) cholesterol and BMD appears to be less profound, but a positive association has been found in some studies [5,10]. While not all studies have identified a relationship between Triglycerides (TG) and BMD, a few larger studies have shown an inverse relationship [7,8,10]. Statins are widely used as cholesterol-lowering drugs, and a recent meta-analysis indicates that statins may help improve and maintain BMD at the lumbar spine, hip and femoral neck, especially in Caucasians and Asians [11]
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