The causal relationship between body composition indexes and primary membranous nephropathy: A bidirectional two-sample Mendelian randomization study.

Genetically predicted higher body weight was causally associated with increased risk of primary membranous nephropathy.

• MRC-IEU dataset: OR = 1.578, 95% CI = 1.047–2.379, IVW p = 0.029
• Neale Lab dataset: OR = 1.745, 95% CI = 1.204–2.529, IVW p = 0.003
• Results were consistent across two independent GWAS sources for weight (n = 797,859)
• Sensitivity analyses verified the robustness of these results

Genetically predicted higher body fat percentage was causally associated with increased risk of primary membranous nephropathy.

• OR = 2.487, 95% CI = 1.349–4.583, IVW p = 0.003
• Body fat percentage GWAS sample size was n = 454,633 in European populations
• This represented the strongest effect size among the body composition indexes examined
• Inverse variance weighted random-effects method was used as the primary analysis

Genetically predicted larger waist circumference was causally associated with increased risk of primary membranous nephropathy.

• Neale Lab dataset: OR = 1.700, 95% CI = 1.042–2.774, IVW p = 0.034
• GIANT dataset: OR = 1.915, 95% CI = 1.030–3.559, IVW p = 0.040
• Results were consistent across two independent GWAS sources for waist circumference (n = 568,740)
• Sensitivity analyses verified the robustness of these results

Genetically predicted larger hip circumference was causally associated with increased risk of primary membranous nephropathy.

• OR = 1.410, 95% CI = 1.021–1.948, IVW p = 0.037
• Hip circumference GWAS sample size was n = 336,601 in European populations
• MR-Egger and weighted median methods were used as supplemental analyses
• Sensitivity analyses verified the robustness of these results

Reverse MR analysis found no causal relationship between primary membranous nephropathy and any of the body composition indexes examined.

• Reverse analysis was conducted for all six body composition indexes: weight, BMI, body fat percentage, waist circumference, hip circumference, and basal metabolic rate
• PMN GWAS sample size was n = 7,979 in European populations
• The bidirectional design allowed assessment of both forward and reverse causal directions
• No statistically significant causal effects were identified in the reverse direction

Body mass index and basal metabolic rate were not found to have a statistically significant causal relationship with primary membranous nephropathy in the forward MR analysis.

• BMI GWAS sample size was n = 461,460 and basal metabolic rate GWAS sample size was n = 454,874 in European populations
• These indexes were included in the analysis alongside weight, body fat percentage, waist circumference, and hip circumference
• Only weight, body fat percentage, waist circumference, and hip circumference showed significant associations with PMN risk
• The IVW random-effects method was used as the primary analysis method