Using a two-sample MR analysis, we investigated the causal relationships between features associated with schizophrenia, major depressive disorder, bipolar disorder, and sarcopenia using data from the GAWS open database. Our findings are as follows: 1) We identified a causal relationship between schizophrenia, major depression, bipolar disorder, and sarcopenia; 2) Conversely, there is also a causal relationship between sarcopenia and schizophrenia and major depression. To our knowledge, this is the first study to analyze the causal relationships between schizophrenia, major depression, bipolar disorder, and features associated with sarcopenia.
Genetic and environmental factors contribute to the development of schizophrenia, involving neurodevelopmental abnormalities, neurotransmitter disorders, and immune dysfunction[27]. Immune dysfunction is crucial in the occurrence and development of the disease, with elevated serum levels of inflammatory factors such as IL-1β and IL-6 observed in most patients[28]. In a clinical study conducted on pregnant rats, one group was injected with polydeoxyribonucleotide, while the control group received saline. Subsequent treatment with N-acetylcysteine (NAC) or omega-3 polyunsaturated fatty acids (PUFAs), both anti-inflammatory agents, resulted in a reduction in the severity of schizophrenia in offspring. Another study by V. Rivi et al.[29] examined the expression levels of NF-κB-related pro-inflammatory factors IL-6, TNF-a, and IL-1β in patients with schizophrenia and found a close association between their levels of onset of schizophrenia. Furthermore, in an upper interaction between dopamine receptor D3 and schizophrenia-associated proteins (DYS), it was found that lower dopamine receptor D3 function led to higher pro-inflammatory cytokines in double-mutant mice compared to single heterozygous mice (DYS +/− and D3 +/−) with down-regulated GRIN1 and GRIN2A mRNA levels. The pathogenesis of major depression mainly involves the dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis, neurotransmitter metabolism disorder, synaptic plasticity, oxidative stress, intestinal flora, neuroinflammation, and other pathological processes[30]. One of its pathological markers is mitochondrial energy metabolism disorder, oxidative stress, and reactive oxygen species (ROS) increase. Therefore, it has gradually become a research hotspot. Refisch et al.[31] proposed that immunoinflammatory disorders are crucial in depression pathogenesis. In patients with poor diets, activation of Toll-like receptor 4 (TLR4) can lead to mitochondrial dysfunction and aggravates the severity of depression. In a case-control study, Sforzin[32] found that the mRNA expression levels of immune-related genes in 122 patients with major depression were higher than those in the control group. Szular[33] discovered that using celecoxib as an anti-inflammatory drug to treat major depression and mania resulted in sound therapeutic effects. Bipolar disorder (BD) is a common mental disorder characterized by alternating episodes of mania and depression that can occur at any age. During a manic episode, the patient's mood is elevated, and speech activity is increased. In the depressive episode, mood and speech activity are reduced speech activity, and symptoms such as fatigue are relieved. Zhang et al.[34] observed significantly increased levels of pro-inflammatory cytokines, particularly elevated IL-6 levels, in patients with bipolar disorder compared to those in the control group.
Sarcopenia is associated with chronic inflammation. Studies have shown that depressive symptoms in older people living in Japanese communities are related to frailty, sarcopenia, and motor syndrome[35]. Furthermore, older adults with weak bodies and reduced muscle mass are prone to major depression[36]. A meta-analysis demonstrated a negative correlation between CRP, IL-6, and TNF-a and muscle strength and mass[37]. In schizophrenia, chronic inflammatory disorders inhibit the ubiquitin-proteasome system, which relies on the activation of insulin-like growth factor 1 (IGF-1), leading to dysregulation of anabolic and muscle homeostasis[38–40].
Additionally, a meta-analysis by Diao et al.[41] showed a close relationship between dietary inflammation and sarcopenia based on 11 studies. Muscle, responsible for over 80% of post-glucose utilization, is crucial in glucose processing. When sarcopenia occurs, decreased muscle mass leads to a chronic imbalance of oxygen and nitrogen (RONS) and pro-oxide substances in the antioxidant system, resulting in increased oxidative damage to cellular components and changes in many signaling pathways. For instance, interleukin-15 (IL-15) levels are affected, and the dysfunction of the PI3K-AKT pathway impairs neutrophil migration and phagocytosis. IL-6 levels also vary with inflammation, damaging the white matter of the brain and causing disruption of brain integration[42], further aggravating the symptoms of schizophrenia. Previous studies[43–47] have established a link between sarcopenia and depression, which is also associated with low muscle strength and poor physical fitness. Therefore, patients with sarcopenia often experience negative symptoms such as depression[48]. Disruption of the dynamic balance of oxidative and antioxidant systems leads to increased levels of microalbumin-positive interneurons (PVIs) and miR-137 in the blood. The latter is associated with cell mitosis, suggesting that mitochondrial autophagy interferes with this process, accumulating damaged mitochondria[49]. These mitochondria are rich in mitochondria and susceptible to oxidative stress. In young mice, damage to PVIs leads to morphological, biochemical, and physiological impairments in the prefrontal cortex, although the degree of injury is reduced after treatment with n-acetylcysteine (NAC). Our findings provide new insight into the causal relationship among schizophrenia, major depression, bipolar disorder, and sarcopenia, as these conditions share similar pathogenic and pathophysiological processes. A sedentary lifestyle, a preference for a high-calorie diet, and disturbances in the immune and oxidative stress systems caused by traumatic stress in childhood were significantly associated with deteriorating skeletal muscle strength, mass, and sarcopenia.
Our study has several strengths:1) Previous studies often focused on the correlation between schizophrenia, major depression, bipolar disorder, and sarcopenia but did not conduct in-depth studies on the causal relationship between them. 2) We included seven sarcopenia-related features as outcome indicators, which had not been included in previous single studies. 3) Schizophrenia, major depression, and bipolar disorder share similar pathogenesis, such as "chronic inflammation and immune system disorder," yet previous studies have not collectively explored the causal relationship between these conditions and sarcopenia. We employed different MR analysis methods to verify the accuracy and validity of the results. Sensitivity analyses, including MR-PRESSO, were performed to assess the causal effect size. However, this study has limitations:1. The use of abstract-level data limited the subgroup analysis, such as investigating schizophrenia, major depressive disorder, and bipolar disorder based on sex, age, and occupation. These diseases manifest differently at various life stages because of social and environmental factors. 2. Most of the people included in this study were of European descent, with only 25.7% of the patients with schizophrenia belonging to other races. Therefore, the results may not be generalizable to people of different races. 3. MR technology is susceptible to "residual bias," and despite implementing multidirectional testing and MR-PRESSO procedures to prevent confounding, some residual bias may be inevitable.
In summary, a significant causal relationship exists between schizophrenia, major depression, and bipolar disorder and the characteristics associated with sarcopenia. Furthermore, our research indicates a potential causal relationship between sarcopenia-related elements, schizophrenia, and bipolar disorder. We found that schizophrenia, major depression, and bipolar disorder can contribute to increased severity of sarcopenia; Conversely, improving sarcopenia-related features (hand grip strength, whole body FFM, right leg FFM, left leg FFM, right arm FFM, left arm FFM, walking pace) can potentially slow the progression of schizophrenia and major depression. However, further studies and extensive GWAS data are necessary to validate these findings.
This two-sample MR analysis provides strong evidence of a significant causal relationship between schizophrenia, major depression, and bipolar disorder and the features associated with sarcopenia. However, a potential causal relationship exists between sarcopenia and the characteristics associated with schizophrenia and bipolar disorder.