Abstract
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.
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.
| Original language | English |
|---|---|
| Article number | e209620 |
| Number of pages | 17 |
| Journal | Neurology |
| Volume | 103 |
| Issue number | 3 |
| Early online date | 10 Jul 2024 |
| DOIs | |
| Publication status | Published - 13 Aug 2024 |
Keywords
- Mendelian Randomization Analysis
- Body Mass Index
- Polymorphism, Single Nucleotide - genetics
- Aged
- Risk Factors
- Genome-Wide Association Study
- Parkinson Disease - genetics - epidemiology
- Female
- Middle Aged
- Humans
- Male