Schizophrenia, Bipolar Disorder, and Alzheimer’s Disease are not Causal Factors of Bone Mineral Density: A Mendelian Randomization Analysis

Abstract

Until recently, it remains unclear whether schizophrenia, bipolar disorder (BD), and Alzheimer's disease (AD) is associated with bone mineral density (BMD). We aimed to investigate the causal effects of schizophrenia, BD and AD on BMD with Mendelian randomization (MR) analysis. Single-nucleotide polymorphisms (SNPs) strongly associated with these three neuropsychiatric diseases as instrumental variables were selected from genome-wide association studies in the MR Base database. We analyzed the effects of these SNPs on the femoral neck BMD (FN-BMD), lumbar spine BMD (LS-BMD) and forearm BMD (FA-BMD), and evaluated the heterogeneities and pleiotropy of these genetic variants. We also evaluated the potential confounding factors in the association between these three neuropsychiatric diseases and the BMD level. It was found that none of these genetic variants were significantly associated with BMD or confounding factors. Using these genetic variants, we did not find statistically significant causal effects of per unit increase in the log-odds of having schizophrenia, BD or AD with FN-BMD, LS-BMD and FA-BMD changes (e.g. schizophrenia and FN-BMD, MR-Egger OR 0.9673, 95% CI 0.8382 to 1.1163, p = 0.6519). The MR results also revealed that directional pleiotropy was unlikely to bias the causality (e.g., schizophrenia and FN-BMD, intercept = 0.0023, p = 0.6887), and no evidence of heterogeneity was found between the genetic variants (e.g., schizophrenia and FN-BMD, MR-Egger Q = 46.1502, I 2 = 0.0899, p = 0.3047). Our MR study did not support causal effects of increased risk of schizophrenia, BD and AD status with BMD level.

Helicobacter pylori Related Diseases and Osteoporotic Fractures (Narrative Review)

“…Notes: Recent genetic studies have challenged some long-assumed risk factors for OP/OF. Mendelian randomization analyses identified BMD [ 413 , 635 , 636 , 637 ], serum estradiol concentrations (in men) [ 638 ] and cigarette smoking [ 639 ] as causal risk factors for OP/OFs, whereas genetic predisposition to lower levels of vitamin D and milk calcium intake [ 635 , 636 , 639 , 640 ], serum testosterone [ 638 ] and inflammation markers [ 641 , 642 ], as well as early menopause; late puberty, chronic (including CVD, DM and IBD) [ 413 , 414 , 643 ] and neuropsychiatric diseases (Alzheimer’s disease, schizophrenia and bipolar disorder) [ 644 ], alcohol consumption [ 645 ] and alcohol dependence [ 639 ] did not show causal effects on BMD and fracture risk. The genetic studies overcome many limitations of the previous observational studies but also contain potential bias; “the Mendelian randomization study design cannot be used to assess whether complications or treatment of those diseases influence fracture risk” [ 636 ].…”

Identification of heel bone mineral density as a risk factor of Alzheimer’s disease by analyzing large-scale genome-wide association studies datasets

“…In addition to AD, recent MR studies have also investigated the causal association between BMD and other neurological disease. Cui and others evaluated the causal effects of schizophrenia and bipolar disorder on BMD at different sites including femoral neck, lumbar spine, and forearm ( Cui et al, 2020 ). However, they identified lack of significant causal effect of schizophrenia and bipolar disorder on BMD ( Cui et al, 2020 ).…”

Mind the Gap: Unraveling the Intricate Dance Between Alzheimer’s Disease and Related Dementias and Bone Health

“…Persistent neuroinflammation in ADRD implies a plausible link to altered bone metabolism and heightened fracture risk, though the precise molecular mediators bridging these processes remain to be unraveled [ 3 , 4 , 6 , 9 , 30 , 48 , 112 ]. While neuroinflammation primarily affects the central nervous system (CNS), it can have systemic effects as well.…”

“…Mouse models of AD have shown low bone mineral density (BMD) and altered osteogenesis and osteoclastogenesis [ 42 ••, 43 , 44 , 45 , 46 , 47 •]. Alternatively, impaired bone health may expedite AD progression, instigating a vicious cycle of disease advancement and deteriorating quality of life [ 5 , 6 , 30 , 48 ]. Neuroinflammation within the brain is one of the hallmarks of ADRD and leads to progression of the and in turn, ADRD can increase the inflammatory response leading to a positive feedback loop resulting in the worsening of the condition [ 49 ].…”