Author(s):
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
Date: 2024
Persistent ID: http://hdl.handle.net/10451/65456
Origin: Repositório da Universidade de Lisboa
Description
Background and objectives: The role of body mass index (BMI) in Parkinson disease (PD) is unclear. Based on the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in PD (Courage-PD) consortium, we used 2-sample Mendelian randomization (MR) to replicate a previously reported inverse association of genetically predicted BMI with PD and investigated whether findings were robust in analyses addressing the potential for survival and incidence-prevalence biases. We also examined whether the BMI-PD relation is bidirectional by performing a reverse MR. 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.
