Novel Insights Into the Causal Effects and Shared Genetics Between Body Fat and Parkinson Disease

Abstract

Aims: Existing observational studies examining the effect of body fat on the risk of Parkinson disease (PD) have yielded inconsistent results. We aimed to investigate this causal relationship at the genetic level.

Methods: We employed two-sample Mendelian randomization (TSMR) to investigate the causal effects of body fat on PD, with multiple sex-specific body fat measures being involved. We performed Bayesian colocalization analysis and cross-trait meta-analysis to reveal pleiotropic genomic loci shared between body mass index (BMI) and PD. Finally, we used the MAGMA tool to perform tissue enrichment analysis of the genome-wide association study hits of BMI.

Results: TSMR analysis suggests that except waist circumference, higher measures of body fatness are associated with a decreased risk of PD, including BMI (OR: 0.83), body fat percentage (OR: 0.69), body fat mass (OR: 0.77), and hip circumference (OR: 0.83). The observed effects were slightly more pronounced in females than males. Colocalization analysis highlighted two colocalized regions (chromosome 3p25.3 and chromosome 17p12) shared by BMI and PD and pointed to some genes as possible players, including SRGAP3, MTMR14, and ADORA2B. Cross-trait meta-analysis successfully identified 10 novel genomic loci, involving genes of TOX3 and MAP4K4. Tissue enrichment analysis showed that BMI-associated genetic variants were enriched in multiple brain tissues.

Conclusions: We found that nonabdominal body fatness exerts a robust protective effect against PD. Our colocalization analysis and cross-trait meta-analysis identified pleiotropic genetic variation shared between BMI and PD, providing new clues for understanding the association between body fat and PD.

Keywords: BMI; Mendelian randomization; Parkinson disease; body fat; colocalization; cross‐trait meta‐analysis.

FIGURE 1

Forest plot of causal effects of body fat indicators on PD. BFM, Whole body fat mass; BFP, body fat percentage; BMI, body mass index; CI, confidence interval; HC, hip circumference; OR, odds ratio; PD, Parkinson disease; WC, waist circumference.

FIGURE 2

Scatter plot of causal effects of body fat measures on PD. (A) Both sexes. (B) Female. (C) Male. BFM, Whole body fat mass; BFP, body fat percentage; BMI, body mass index; HC, hip circumference; IVW, inverse variance weighted; PD, Parkinson disease; WC, waist circumference; WM, weighted median.

FIGURE 3

Two colocalized regions between BMI and PD. The x‐axis represents the genomic coordinates and the y‐axis represents the negative log₁₀ transform p value for each genetic variant. BMI, Body mass index; PD, Parkinson disease.

FIGURE 4

Cross‐trait meta‐analysis and enrichment analysis. (A) Manhattan plot of FUMA analysis of BMI and PD. The x‐axis is the chromosomal position of SNPs, and the y‐axis is the significance of the SNPs (−log₁₀P). (B, C). The genomic loci of BMI and PD. (D) Enrichment analysis of BMI.