Two-sample Mendelian randomization analysis found causal relationships between limb fat distribution and ADHD and MDD, with right arm and left leg fat mass negatively correlated and left arm and right leg fat mass positively correlated with these disorders, while no significant causal relationships were found for schizophrenia or bipolar disorder.
Key Findings
Results
Right arm fat mass was significantly negatively correlated with ADHD in Mendelian randomization analysis.
The inverse variance weighting (IVW) method was used as the primary analytical approach.
The association reached statistical significance at P < .05.
Sensitivity analyses using MR-Egger, weighted median, simple mode, and weighted mode methods were conducted to confirm robustness.
GWAS summary data from a European population were used as the source data.
Results
Left leg fat mass was significantly negatively correlated with ADHD.
The negative correlation was identified using two-sample MR analysis with IVW as the primary estimator.
The association reached statistical significance at P < .05.
This finding was consistent with the negative direction observed for right arm fat mass and ADHD.
Sensitivity analyses were performed to confirm the robustness of the findings.
Results
Left arm fat mass was significantly positively correlated with ADHD.
The positive correlation was statistically significant at P < .05.
This contrasted directionally with the negative association found for right arm fat mass and ADHD.
The finding was based on GWAS summary data from a European population analyzed via two-sample MR.
Multiple sensitivity analysis methods were used to validate the result.
Results
Right leg fat mass was significantly positively correlated with ADHD.
The association reached statistical significance at P < .05.
This directionally contrasted with the negative association found for left leg fat mass and ADHD.
Results were reported using IVW as the primary method with additional sensitivity analyses.
The asymmetric pattern of associations across limb sides was a notable feature of the findings.
Results
Limb fat mass showed a significant causal relationship with major depressive disorder (MDD), with right arm and left leg fat mass negatively correlated and left arm and right leg fat mass positively correlated.
The causal relationship between body fat mass and MDD was significant at P < .05.
The directional pattern of associations mirrored that found for ADHD, with the same asymmetry across body sides.
IVW estimates were the primary results reported, supported by MR-Egger, weighted median, simple mode, and weighted mode sensitivity analyses.
GWAS summary data from a European population were used.
Results
No significant causal relationship was found between limb fat mass and schizophrenia or bipolar disorder.
Both schizophrenia and bipolar disorder were among the 4 major mental disorders examined in the study.
Associations did not reach statistical significance (P ≥ .05) for either condition.
The same two-sample MR methodology and GWAS data sources were applied as for ADHD and MDD analyses.
Sensitivity analyses were also conducted for these disorders.
Methods
The study used a two-sample Mendelian randomization design drawing on GWAS summary data for limb fat mass and mental disorders in European populations.
GWAS summary data on limb fat mass and four major mental disorders (ADHD, MDD, schizophrenia, and bipolar disorder) were utilized.
The study population was of European ancestry.
IVW was the primary analytical method, with MR-Egger, weighted median, simple mode, and weighted mode as supplementary sensitivity analyses.
The MR design was employed to assess causal relationships while minimizing confounding.
Wang H, Cheng Y, Wang T, Liu H, Dou L, Sun W, et al.. (2026). The causal relationships between limb fat distribution and mental disorders: A Mendelian randomization study.. Medicine. https://doi.org/10.1097/MD.0000000000046759