Causal associations of brain structure with bone mineral density: a large-scale genetic correlation study

Abstract

In this study, we aimed to investigate the causal associations of brain structure with bone mineral density (BMD). Based on the genome-wide association study (GWAS) summary statistics of 1 325 brain imaging-derived phenotypes (BIDPs) of brain structure from the UK Biobank and GWAS summary datasets of 5 BMD locations, including the total body, femoral neck, lumbar spine, forearm, and heel from the GEFOS Consortium, linkage disequilibrium score regression (LDSC) was conducted to determine the genetic correlations, and Mendelian randomization (MR) was then performed to explore the causal relationship between the BIDPs and BMD. Several sensitivity analyses were performed to verify the strength and stability of the present MR outcomes. To increase confidence in our findings, we also performed confirmatory MR between BIDPs and osteoporosis. LDSC revealed that 1.93% of BIDPs, with a false discovery rate (FDR) < 0.01, were genetically correlated with BMD. Additionally, we observed that 1.31% of BIDPs exhibited a significant causal relationship with BMD (FDR < 0.01) through MR. Both the LDSC and MR results demonstrated that the BIDPs “Volume of normalized brain,” “Volume of gray matter in Left Inferior Frontal Gyrus, pars opercularis,” “Volume of Estimated Total Intra Cranial” and “Volume-ratio of brain segmentation/estimated total intracranial” had strong associations with BMD. Interestingly, our results showed that more left BIDPs were causally associated with BMD, especially within and around the left frontal region. In conclusion, a part of the brain structure causally influences BMD, which may provide important perspectives for the prevention of osteoporosis and offer valuable insights for further research on the brain-bone axis.

Causal relationships involving brain imaging-derived phenotypes based on UKB imaging cohort: a review of Mendelian randomization studies

“…Observational evidence supports that neurodegenerative diseases are associated with a higher prevalence of osteoporosis ( Raglione et al, 2011 ; Simonsen et al, 2016 ; Caplliure-Llopis et al, 2020 ; Kumar et al, 2021 ). Guo et al conduct a study to investigate the genetic correlations and causal associations between 1,325 BIDPs and BMD at 5 different locations (total body, lumbar spine, femoral neck, forearm, and heel) ( Guo et al, 2023 ). As a first step, linkage disequilibrium score regression (LDSC) was used to identify 1.93% of BIDPs showing significant genetic association with BMD.…”

Low bone mineral density is associated with gray matter volume decrease in UK Biobank

“…Although our study design does not allow us to draw any causal conclusions, it adds to the body of literature showing that bone health could affect brain health and vice-versa. A possible causal connection of brains influencing the bones has been recently discovered in a Mendelian randomization study (Guo et al, 2023). Further studies that would investigate interrelated longitudinal changes in bone and brain health are necessary to expand our knowledge of the bone-brain crosstalk.…”

Causal effect of the gut microbiota on the risk of psychiatric disorders and the mediating role of immunophenotypes

“…To guarantee the premise of independence, IVs were pruned with linkage disequilibrium (LD) r 2 > 0.001 in the 1000 Genomes European data within 10 Mb windows [34]. To compensate for missing SNPs, those with strong linkage disequilibrium (r 2 > 0.8) were utilized [35].…”