Summarized data only for the European population were adopted to remove the bias of ethnic heterogeneity. Consequently, we performed a Multivariable Mendelian randomization (MVMR) analysis to eliminate the effect of BMI confounder. A recent MR study based on GWAS also demonstrated a causal relationship between BMI and estimated BMD (eBMD). In addition, several studies verified that low BMI was associated with increased fracture risk and low BMD. Given the various incidence and severity of different fracture sites in patients with psychiatric disorders, we further explored the causal effect of schizophrenia on site-specific fractures and BMD. Thus, we performed a two-sample MR, based on genome-wide GWAS summary statistics, to investigate the causal effect of schizophrenia on fractures and BMD. However, few studies investigated the causal association of schizophrenia with fractures and BMD in the population coming from European ancestry. Recent large-scale genome-wide association studies (GWAS) have identified the multiple genetic variants associated with complex human traits or diseases, including schizophrenia, which implements two-sample MR by using the variants as the instrumental variables (IVs) with increased statistical power to detect the potential causal association of schizophrenia with other traits. While conducting a randomized controlled trial (RCT) to determine the causal factors is not feasible, Mendelian Randomization (MR), a widely used method of causal inference, is applied to infer the causality of risk factor “exposures” to disease “outcomes” in case to the circumvent confounding bias and reverse causation. Thus far, the evidence of the relationship between schizophrenia and fracture mainly comes from the relevant research or clinical observation, and the confusion triggered by intermediary factors and possible reverse causal relationship hinders the exploration of causal effect. Therefore, the causal association of schizophrenia with fracture and osteoporosis should be worth investigating. In patients with schizophrenia, other risk factors for osteoporosis and fractures such as lack of physical activity, diabetes, smoking, excessive drinking and vitamin D deficiency are more prevalent, which may further contribute to the occurrence and development of schizophrenia. Previous studies have reported that hyperprolactinemia caused by the long-term use of antipsychotics accelerates bone turnover, which results in hypothalamic-pituitary-gonadal axis mediating osteopenia so as to increase the risk of fracture. However, the pathogenesis of osteoporosis and fracture in patients with schizophrenia are not clearly defined. Compared with the general population, patients with schizophrenia experience poor general health outcomes, including increased risks of osteoporosis which is characterized by abnormally low bone mineral density (BMD), and fracture, especially hip fracture. Schizophrenia is a severe, complex and neuropsychiatric disorder with marked functional impairment posing a considerable societal burden, affecting about 1% of the world’s population. The current finding confirmed that schizophrenia was causally associated with the fractures of skull, face and femur as well as eBMD, which might remind psychiatrists to pay close attention to the fracture risk in schizophrenic patients when formulating their treatment strategies. However, no causal effect of schizophrenia on fracture or BMD in other parts was detected. Sensitivity analyses showed similar results. These causal effects still existed after adjusting for BMI. Result from inverse variance weighting (IVW) method provided evidence schizophrenia increased the risk of fractures of skull and facial bones and femur, whereas, decreased the level of eBMD. Multivariable Mendelian randomization (MVMR) analysis was performed to minimize the confounding effect of body mass index (BMI). Two-sample MR was utilized, based on instrumental variables from large genome-wide association studies (GWAS) of schizophrenia as exposure, to identify the causal association of schizophrenia with mixed fractures, fractures at different body sites (including skull and facial bones, shoulder and upper arm, wrist and hand, and femur) and BMDs of forearm (FA), femoral neck (FN), lumbar spine (LS) and estimated BMD (eBMD). This study aimed to test the causal effects between schizophrenia and fractures as well as aberrant BMD by conducting Mendelian randomization (MR) analyses. Schizophrenia was clinically documented to co-occur with fractures and aberrant bone mineral density (BMD), but the potential causal relationship remained unclear.
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