Association of Body Mass Index and Parkinson Disease: A Bidirectional Mendelian Randomization Study.
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Domenighetti Cloé, Sugier Pierre-Emmanuel, Ashok Kumar Sreelatha Ashwin, Schulte Claudia, Grover Sandeep, Portugal Berta, Lee Pei-Chen, May Patrick, Bobbili Dheeraj, Radivojkov Blagojevic Milena, Lichtner Peter, Singleton Andrew B, Hernandez Dena, Edsall Connor, Mellick George D, Zimprich Alexander A, Pirker Walter, Rogaeva Ekaterina A, Lang Anthony E, Koks Sulev, Taba Pille, Lesage Suzanne, Brice Alexis, Corvol Jean-Christophe, Chartier-Harlin Marie-Christine, Mutez Eugenie, Brockmann Kathrin, Deutschlander Angela B, Hadjigeorgiou Georgios M, Dardiotis Efthimios, Stefanis Leonidas, Simitsi Athina Maria, Valente Enza Maria, Petrucci Simona, Straniero Letizia, Zecchinelli Anna L, Pezzoli Gianni, Brighina Laura, Ferrarese Carlo, Annesi Grazia, Quattrone Andrea, Gagliardi Monica, Matsuo Hirotaka, Nakayama Akiyoshi, Hattori Nobutaka, Nishioka Kenya, Chung Sun Ju, Kim Yun Joong, Kolber Pierre, Van De Warrenburg Bart P C, Bloem Bastiaan R, Toft Mathias, Pihlstrøm Lasse, Correia Guedes Leonor, Ferreira Joaquim J, Bardien Soraya, Carr Jonathan, Tolosa Eduardo, Ezquerra Mario, Pastor Pau, Diez-Fairen Monica, Wirdefeldt Karin, Pedersen Nancy L, Ran Caroline, Belin Andrea C, Puschmann Andreas, Hellberg Clara, Clarke Carl E, Morrison Karen E, Tan Manuela M, Krainc Dimitri, Burbulla Lena F, Farrer Matthew, Kruger Rejko, Gasser Thomas, Sharma Manu, Elbaz Alexis, Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease (COURAGE-PD) Consortium
Аннотация
METHODS: We used summary statistics from a genome-wide association study (GWAS) to extract the association of 501 single-nucleotide polymorphisms (SNPs) with BMI and from the Courage-PD and international Parkinson Disease Genomics Consortium (iPDGC) to estimate their association with PD. Analyses are based on participants of European ancestry. We used the inverse-weighted method to compute odds ratios (ORIVW per 4.8 kg/m2 [95% CI]) of PD and additional pleiotropy robust methods. We performed analyses stratified by age, disease duration, and sex. For reverse MR, we used SNPs associated with PD from 2 iPDGC GWAS to assess the effect of genetic liability toward PD on BMI.
RESULTS: Summary statistics for BMI are based on 806,834 participants (54% women). Summary statistics for PD are based on 8,919 (40% women) cases and 7,600 (55% women) controls from Courage-PD, and 19,438 (38% women) cases and 24,388 (51% women) controls from iPDGC. In Courage-PD, we found an inverse association between genetically predicted BMI and PD (ORIVW 0.82 [0.70-0.97], p = 0.012) without evidence for pleiotropy. This association tended to be stronger in younger participants (≤67 years, ORIVW 0.71 [0.55-0.92]) and cases with shorter disease duration (≤7 years, ORIVW 0.75 [0.62-0.91]). In pooled Courage-PD + iPDGC analyses, the association was stronger in women (ORIVW 0.85 [0.74-0.99], p = 0.032) than men (ORIVW 0.92 [0.80-1.04], p = 0.18), but the interaction was not statistically significant (p-interaction = 0.48). In reverse MR, there was evidence for pleiotropy, but pleiotropy robust methods showed a significant inverse association.
DISCUSSION: Using an independent data set (Courage-PD), we replicate an inverse association of genetically predicted BMI with PD, not explained by survival or incidence-prevalence biases. Moreover, reverse MR analyses support an inverse association between genetic liability toward PD and BMI, in favor of a bidirectional relation.