Department of Psychiatry, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
Department of Radiology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China.
CNS Neurosci Ther. 2024 Nov;30(11):e70132. doi: 10.1111/cns.70132.
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.
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.
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.
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.
现有的观察性研究检查体脂肪对帕金森病（PD）风险的影响得出的结果并不一致。我们旨在在遗传水平上研究这种因果关系。
我们采用两样本孟德尔随机化（TSMR）来研究体脂肪对 PD 的因果影响，涉及多种性别特异性体脂肪测量。我们进行了贝叶斯共定位分析和跨性状荟萃分析，以揭示体重指数（BMI）和 PD 之间共享的多效性基因组位置。最后，我们使用 MAGMA 工具对 BMI 的全基因组关联研究命中进行组织富集分析。
TSMR 分析表明，除腰围外，较高的体脂水平与 PD 风险降低相关，包括 BMI（OR：0.83）、体脂百分比（OR：0.69）、体脂量（OR：0.77）和臀围（OR：0.83）。在女性中观察到的效果略高于男性。共定位分析突出了 BMI 和 PD 共享的两个共定位区域（染色体 3p25.3 和染色体 17p12），并指出了一些可能的基因，包括 SRGAP3、MTMR14 和 ADORA2B。跨性状荟萃分析成功鉴定了 10 个新的基因组位置，涉及 TOX3 和 MAP4K4 基因。组织富集分析表明，与 BMI 相关的遗传变异在多个脑组织中富集。
我们发现非腹部体脂肪对 PD 具有强大的保护作用。我们的共定位分析和跨性状荟萃分析确定了 BMI 和 PD 之间共享的多效性遗传变异，为理解体脂肪与 PD 之间的关联提供了新的线索。
