Abstract summary 

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.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 (OR per 4.8 kg/m [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.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 (OR 0.82 [0.70-0.97], = 0.012) without evidence for pleiotropy. This association tended to be stronger in younger participants (≤67 years, OR 0.71 [0.55-0.92]) and cases with shorter disease duration (≤7 years, OR 0.75 [0.62-0.91]). In pooled Courage-PD + iPDGC analyses, the association was stronger in women (OR 0.85 [0.74-0.99], = 0.032) than men (OR 0.92 [0.80-1.04], = 0.18), but the interaction was not statistically significant (-interaction = 0.48). In reverse MR, there was evidence for pleiotropy, but pleiotropy robust methods showed a significant inverse association.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.

Authors & Co-authors:  Domenighetti Cloé C Sugier Pierre-Emmanuel PE Ashok Kumar Sreelatha Ashwin A Schulte Claudia C Grover Sandeep S Portugal Berta B Lee Pei-Chen PC May Patrick P Bobbili Dheeraj D Radivojkov Blagojevic Milena M Lichtner Peter P Singleton Andrew B AB Hernandez Dena D Edsall Connor C Mellick George D GD Zimprich Alexander A AA Pirker Walter W Rogaeva Ekaterina A EA Lang Anthony E AE Koks Sulev S Taba Pille P Lesage Suzanne S Brice Alexis A Corvol Jean-Christophe JC Chartier-Harlin Marie-Christine MC Mutez Eugenie E Brockmann Kathrin K Deutschlander Angela B AB Hadjigeorgiou Georgios M GM Dardiotis Efthimios E Stefanis Leonidas L Simitsi Athina Maria AM Valente Enza Maria EM Petrucci Simona S Straniero Letizia L Zecchinelli Anna L AL Pezzoli Gianni G Brighina Laura L Ferrarese Carlo C Annesi Grazia G Quattrone Andrea A Gagliardi Monica M Matsuo Hirotaka H Nakayama Akiyoshi A Hattori Nobutaka N Nishioka Kenya K Chung Sun Ju SJ Kim Yun Joong YJ Kolber Pierre P Van De Warrenburg Bart P C BPC Bloem Bastiaan R BR Toft Mathias M Pihlstrøm Lasse L Correia Guedes Leonor L Ferreira Joaquim J JJ Bardien Soraya S Carr Jonathan J Tolosa Eduardo E Ezquerra Mario M Pastor Pau P Diez-Fairen Monica M Wirdefeldt Karin K Pedersen Nancy L NL Ran Caroline C Belin Andrea C AC Puschmann Andreas A Hellberg Clara C Clarke Carl E CE Morrison Karen E KE Tan Manuela M MM Krainc Dimitri D Burbulla Lena F LF Farrer Matthew M Kruger Rejko R Gasser Thomas T Sharma Manu M Elbaz Alexis A

Study Outcome 

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