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

IF 4.8 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics Pub Date : 2024-11-22 DOI:10.1111/cns.70132

Qian Zhao, Dongming Liu, Ancha Baranova, Hongbao Cao, Fuquan Zhang

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引用次数: 0

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.

Abstract Image

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体脂与帕金森病之间的因果效应和共同遗传学的新见解。

目的：现有的观察性研究探讨了身体脂肪对帕金森病（PD）患病风险的影响，但结果并不一致。我们旨在从遗传学层面研究这种因果关系：我们采用双样本孟德尔随机法（TSMR）研究体脂对帕金森病的因果效应，其中涉及多种性别特异性体脂测量指标。我们进行了贝叶斯共定位分析和跨性状荟萃分析，以揭示体质指数（BMI）与帕金森病之间共有的多效基因组位点。最后，我们使用 MAGMA 工具对 BMI 的全基因组关联研究结果进行了组织富集分析：TSMR分析表明，除腰围外，身体脂肪含量越高，罹患帕金森病的风险越低，包括体重指数（OR：0.83）、体脂百分比（OR：0.69）、体脂质量（OR：0.77）和臀围（OR：0.83）。观察到的影响在女性中比在男性中更明显。共定位分析强调了BMI和PD共有的两个共定位区域（染色体3p25.3和染色体17p12），并指出一些基因可能参与其中，包括SRGAP3、MTMR14和ADORA2B。跨性状荟萃分析成功地发现了10个新的基因组位点，涉及TOX3和MAP4K4基因。组织富集分析表明，与BMI相关的基因变异富集在多个脑组织中：结论：我们发现，非腹部体脂对脊髓灰质炎有很强的保护作用。我们的共定位分析和跨性状荟萃分析发现了BMI和帕金森病之间共有的多向遗传变异，为理解体脂与帕金森病之间的关联提供了新线索。

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来源期刊

CNS Neuroscience & Therapeutics 医学-神经科学

CiteScore

7.30

自引率

12.70%

发文量

240

审稿时长

2 months

期刊介绍： CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.