Osteoporosis and sarcopenia-related traits: A bi-directional Mendelian randomization study

Abstract

BackgroundWith the advancement of world population aging, age-related osteoporosis (OP) and sarcopenia (SP) impose enormous clinical and economic burden on society. Evidence from accumulating studies indicates that they mutually influence one another. However, an observational study may be affected by potential confounders. Meanwhile, a Mendelian randomization (MR) study can overcome these confounders to assess causality.ObjectivesThe aim of this study was to evaluate the causality between OP and SP, informing new strategies for prevention, diagnosis, and treatment of osteosarcopenia.MethodsInstrumental variables (IVs) at the genome‐wide significance level were obtained from published summary statistics, and the inverse variance weighted method and several other MR methods were conducted to evaluate the bi-directional causality between SP and OP. Myopia was analyzed as a negative control outcome to test the validity of IVs.ResultsFemoral neck bone mineral density (FN BMD), lumbar spine BMD (LS BMD), and forearm BMD (FA BMD) had a direct causal effect on appendicular lean mass (ALM) [FA BMD-related analysis: odds ratio (OR) = 1.028, 95% confidence interval (CI) = (1.008,1.049), p = 0.006; FN BMD-related analysis: OR (95% CI) = 1.131 (1.092,1.170), p = 3.18E-12; LS BMD-related analysis: OR (95% CI) = 1.080 (1.062,1.098), p = 2.86E-19]. ALM had a significant causal effect on LS BMD [OR (95% CI) = (1.033,1.147), p = 0.001]. There was no evidence for causal association between BMD and low grip strength.ConclusionsOP and SP might mutually have a significant causal effect on each other. Our results supported the idea that the patient with severe OP was more susceptible to lose ALM and severe ALM loss might reduce LS BMD.

GWAS-informed data integration and non-coding CRISPRi screen illuminate genetic etiology of bone mineral density

“…Much research has focused on the relationships between body composition and BMD. Briefly, muscle mass, strength, and bone density have generally been found to correlate positively across groups 4,[60][61][62][63][64][65][66] likely sharing a causal relationship [67][68][69] , while the association between adiposity and BMD is more complex with some evidence of positive correlations between adiposity and the BMD of weight-bearing bones 64,66,67,70,71 that may attenuate or even reverse after accounting for adiposity type 65,[72][73][74] , at extreme ranges of adiposity 66,74,75 , or in certain age and sex-based subpopulations 64,67,73,76 . The complexity of these prior results coincides well with our observation of effect direction heterogeneity across signals fine-mapped for both body-composition traits and BMD.…”

Higher Risk of Rheumatoid Arthritis in Patients With Chronic Rhinosinusitis: Prospective Association in the U.K. Biobank and Genetic Evidence by Mendelian Randomization Analysis

“…If there was horizontal pleiotropy, the MR-Egger estimation would be the main effect size. 34 In this study, we used Two Sample MR packages (version 0.5.6) to perform the MR analysis in R (version 4.2.1). The statistical significance level was set at p < .05.…”

Targeting cardiac and cerebrovascular risks of sarcopenia: Is it time to screen for muscle health?

“…Others have linked sarcopenia to elevated inflammatory markers as predictors of CVD 6 . Two Mendelian randomization studies utilizing the UK Biobank and other datasets also found individual components of sarcopenia, such as low appendicular lean mass (ALM) and handgrip strength (HGS), to be independent causal risk factors for coronary artery disease and myocardial infarction (MI), though findings were less consistent for stroke 7,8 . Despite the associations with surrogate markers and the intuitive pathophysiology, studies on the direct association of sarcopenia with cardiovascular events have shown mixed results.…”

“…6 Two Mendelian randomization studies utilizing the UK Biobank and other datasets also found individual components of sarcopenia, such as low appendicular lean mass (ALM) and handgrip strength (HGS), to be independent causal risk factors for coronary artery disease and myocardial infarction (MI), though findings were less consistent for stroke. 7,8 Despite the associations with surrogate markers and the intuitive pathophysiology, studies on the direct association of sarcopenia with cardiovascular events have shown mixed results. For example, a 2020 UK Biobank study found sarcopenia, defined by low muscle mass and strength using the European Working Group on Sarcopenia in Older People 2 (EWGSOP2) criteria, not to be associated with incident CVD (MI or stroke).…”