Introduction
Schizophrenia is a severe, complex and neuropsychiatric disorder with marked functional impairment posing a considerable societal burden [
1,
2], affecting about 1% of the world’s population. 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 [
3‐
5]. However, the pathogenesis of osteoporosis and fracture in patients with schizophrenia are not clearly defined. 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 [
6,
7]. 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 [
8,
9], which may further contribute to the occurrence and development of schizophrenia. Therefore, the causal association of schizophrenia with fracture and osteoporosis should be worth investigating.
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. 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 [
10]. Recent large-scale genome-wide association studies (GWAS) have identified the multiple genetic variants associated with complex human traits or diseases, including schizophrenia [
11‐
13], 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.
However, few studies investigated the causal association of schizophrenia with fractures and BMD in the population coming from European ancestry. 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. Given the various incidence and severity of different fracture sites in patients with psychiatric disorders [
4], we further explored the causal effect of schizophrenia on site-specific fractures and BMD. In addition, several studies verified that low BMI was associated with increased fracture risk and low BMD [
14,
15]. A recent MR study based on GWAS also demonstrated a causal relationship between BMI and estimated BMD (eBMD) [
16]. Consequently, we performed a Multivariable Mendelian randomization (MVMR) analysis to eliminate the effect of BMI confounder.
Discussion
Most of previous studies on schizophrenia increasing the risk of fracture were observational studies, whose results might be affected by behavioral factors such as vitamin D deficiency, physical activity, antipsychotics and diet [
29‐
31]. To the best of our knowledge, the present study was the first MR study to systematically investigate the causality of genetic liability to schizophrenia with fracture and BMD in identical ancestry. Our results showed that schizophrenia was positively associated with the fracture of the skull and facial, and femur, whereas, inversely associated with eBMD. Prevention, early detection, and intervention are required.
A previous MR study found no causal relationship between schizophrenia and BMD; however, the lineage of a schizophrenia GWAS (Europe and Asia) and BMD GWAS (only Europe) was not uniform [
32]. We only extracted European GWAS, to avoid the defect of unified ancestors, and identified that schizophrenia reduced the level of eBMD. The present result was also supported by a series of previous studies. For example, a cross-sectional study suggested a higher prevalence of osteoporosis and low bone mass in schizophrenia patients by measuring eBMD [
3]. A meta-analysis in Western countries also showed that BMD level in patients with schizophrenia was significantly lower than that in age- and sex-matched controls [
33]. Moreover, we found that schizophrenia was related to increased FA BMD. We believed that this result should be worth pondering because of the small sample size of FA BMD which might cause more susceptibility to environmental factors and the use of proxy SNP. Thus, our findings still needed to be further validated in larger samples and other populations.
Our study also found that schizophrenia had a genetic causal effect on the fracture of femur which was a position of the hip joint fracture. A recent 10-year cohort study suggested that the risk of hip fracture in schizophrenic patients was higher than that in the control group, while no difference was found in wrist fracture [
5]. The evidence of schizophrenics prone to hip fractures compared to the general population also existed in a large population-cohort study [
31]. Moreover, patients with comorbid schizophrenia had increased risks of unconventional discharge, adverse events and death after femoral fracture surgery, which might impose additional economic burdens on the healthcare system [
34]. Currently, few studies on the fracture of skull and facial of schizophrenia were implemented, and we first discovered the causal effect of schizophrenia on the fracture of skull and facial. A cross-sectional study with a large sample showed that the proportion of primary nasal fractures in patients with mental illness was much higher and more severe [
35]. Additionally, genetic variation such as apolipoprotein E, which was associated with the risk of Alzheimer’s disease, has shown a variable interaction with mild traumatic brain injury [
36]. We speculated that there might be shared genetic variation between mental disorders that could help to explain the susceptibility to the fracture of skull.
It was worth discussing the reasons for the increased fracture and reduction of eBMD in schizophrenia patients. The possible mechanism underlying involved altered levels of inflammatory cytokines in schizophrenia to cause osteoclast formation and then increase the risk of fracture. Abnormal levels of inflammatory factors including C-reactive protein, transforming growth factor α(TGF- α), interleukin-6 (IL-6) and insulin-like growth factor (IGF-I) in schizophrenia were confirmed in the observational and MR studies [
11,
37,
38]. Meanwhile, IGF-I was produced by osteoblasts and was involved in bone metabolism [
39], TNF-α and IL-6 also partaken in bone resorption [
40], ultimately leading to deficiency-related bone loss [
41,
42]. With the IVs we selected, rs12833624, rs1615350, rs4947336, rs9258375, rs13195402, rs13195636, rs1264347, rs9461856, rs3795310, rs8192589 and rs3814883 were related to the lymphocytes, eosinophils and deficiency of IGA, which indirectly supported that inflammatory reaction might mediate schizophrenia and increase the risk of fracture.
In addition to the inflammatory process, a disturbed hypothalamic-pituitary-adrenocortical (HPA) axis might be another hypothesis for the risk of fracture in schizophrenia. Chronic psychological stress in schizophrenia affected the HPA axis, sympathetic nervous system, endocrine and immune factors, inhibited the secretion of gonadal hormone and growth hormone, and increased inflammatory cytokines, which might finally lead to bone loss by inhibiting bone formation and stimulating bone absorption [
43]. Besides, the endocrine cannabinoid system played an important role in the development of schizophrenia, Cannabinoid receptors type 1 has been widely found to be involved in regulating the HPA axis in the meso solute pathway [
44]. HPA axis activity was increased in patients with mental disorders, which was particularly common at the time of onset [
45]. Hence, we speculated that schizophrenic patients might, directly and indirectly, affect bone cells through HPA axis, thus increasing fracture risk and reducing BMD.
The advantage of this study derived from the manipulation of MR, to minimize the confounding factors and reverse causal effects in observational studies, and a series of sensitivity analysis methods were considered to obtain robust results, weakening the limitations of heterogeneity and horizontal pleiotropy. The cases of fractures in various parts were diagnosed according to the international standard ICD-10 rather than self-reported. All individuals in the study unified into European populations to avoid ethnic mixing. Otherwise, it might be inaccurate to extend our conclusions to other populations. Although we had strenuously collected the largest sample of open fracture GWAS in all parts, the number of cases was still limited to accurately determine the level of its causal effect. Thus, these findings still needed to be confirmed. In addition, our findings were identified on heel eBMD which did not represent BMD, despite ultrasound eBMD was increasingly recognized as a valid alternative to DXA [
46] and successfully wielded in previous studies [
16,
18,
47]. Though previous observational studies believed that schizophrenia would increase the risk of fracture and reduce BMD [
5,
29,
48], our results still needed to be confirmed in future studies. Finally, only BMI was considered in MVMR as it was mostly correlated with the selected IVs, but the effects of other confounding factors such as age, and vitamin D were not included, which was worth further investigated.
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