Tang, Bowen, Shi, Huwenbo, Alfredsson, Lars, Klareskog, Lars, Padyukov, Leonid, and Jiang, Xia
Objective: To investigate the association between obesity‐related traits and risk of rheumatoid arthritis (RA). Methods: We conducted genetic correlation analysis and a 2‐sample Mendelian randomization (MR) study, using genome‐wide genetic data based on >850,000 individuals of European ancestry. Summary statistics were collected from the largest genome‐wide association study conducted to date for body mass index (BMI; n = 806,810), waist‐to‐hip ratio (WHR; n = 697,734), WHR adjusted for BMI (WHRadjBMI; n = 694,649), and RA (ncase = 14,361, ncontrol = 43,923). We conducted cross‐trait linkage disequilibrium score regression and ρ‐HESS analyses to quantify genetic correlation between pairs of traits (causal overlap). For each obesity‐related exposure, we utilized independent, genome‐wide significant single‐nucleotide polymorphisms (P < 5 × 10−9) as instruments to perform MR analysis (causal relationship). We interrogated the causal relationship both in the general population and in a sex‐specific manner and calculated odds ratios (ORs) and 95% confidence intervals (95% CIs). Sensitivity analyses were performed to validate MR model assumptions. Results: Despite a negligible overall genetic correlation between the 3 obesity‐related traits and RA, we found significant local genetic correlations at several regions on chromosome 6 (positions 28–29M, 30–35M, and 50–52M), highlighting a shared genetic basis. We further observed an increased risk of RA per SD increment (4.8 kg/m2) in genetically predicted BMI (OR 1.22 [95% CI 1.09–1.37]). The effect was consistent across sensitivity analyses and comparable between sexes (OR 1.22 [95% CI 1.04–1.44] in male subjects and 1.19 [95% CI 1.04–1.36] in female subjects). However, we did not find evidence supporting a causal role of either WHR (OR 0.98 [95% CI 0.84–1.14]) or WHRadjBMI (OR 0.90 [95% CI 0.79–1.04]) in RA. Conclusion: Genetically predicted BMI significantly increases RA risk. Future studies are needed to understand the biologic mechanisms underlying this link. [ABSTRACT FROM AUTHOR]