肥胖与大脑皮质厚度之间的遗传关联：联合遗传相关性、多性状荟萃分析和孟德尔随机化
Genetic Associations between Obesity and Brain Cortical Thickness: Combined Genetic Correlation, Multi-Trait Meta-Analysis, and Mendelian Randomization.
作者信息
Chen Jiankun, Pan Simin, Tan Yingfei, Wu Yuan, Huang Taoliang, Huang Bin, Wu Shiheng, Xie Changcai, Cai Shubin, Li Jiqiang, Lu Yue, Chen Yu
机构信息
State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences), Guangzhou, China.
The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China.
出版信息
Neuroendocrinology. 2025;115(3-4):308-314. doi: 10.1159/000543574. Epub 2025 Jan 20.
INTRODUCTION
Obesity may lead to cognitive impairment and neuropsychiatric disorders, which are associated with changes in the brain cortical structure, particularly in cortical thickness. However, the exact genetic association between obesity and brain cortical thickness remains inconclusive. We aimed to identify the relationship between obesity-related traits (body mass index [BMI], waist-hip ratio [WHR], and waist-hip ratio adjusted for BMI [WHRadjBMI]) and brain cortical thickness.
METHODS
Leveraging summary statistics of large-scale GWAS(s) conducted in European-ancestry populations on BMI (N = 806,834), WHR (N = 697,734), WHRadjBMI (N = 694,649), and brain cortex thickness (N = 33,709), we performed GWAS combining genetic correlation, multi-trait meta-analysis, and Mendelian randomization analysis.
RESULTS
Our findings revealed a strong genetic correlation between BMI and brain cortical thickness (rg = -0.0542, p = 0.0435), and a significant result was also observed for WHR and brain thickness (rg = -0.0744, p = 0.009). In addition, we identified three loci between obesity-related traits. Mendelian randomization analysis supported the causal role of BMI (inverse-variance-weighted [IVW] beta = -0.006, 95% CI = -0.011 to -3.85E-04; weighted median beta = -0.006, 95% CI = -0.013 to -0.002), WHR (IVW beta = -0.011, 95% CI = -0.018 to -0.005; weighted median beta = -0.008, 95% CI = -0.018 to -0.003), and WHRadjBMI (IVW beta = 0.011, 95% CI = -0.018 to -0.005; weighted median beta = -0.008, 95% CI = -0.018 to -0.002) in brain cortical thickness.
CONCLUSION
This study has shown that genetically predicted obesity-related traits have a causal relationship with reduced cortical thickness. These findings provide genetic evidence for a link between obesity and structural changes in the brain and suggest that obesity may be associated with neuropsychiatric disorders by affecting brain structure, particularly cortical thickness.
引言
肥胖可能导致认知障碍和神经精神疾病，这与大脑皮质结构的变化有关，尤其是皮质厚度的变化。然而，肥胖与大脑皮质厚度之间的确切遗传关联仍无定论。我们旨在确定肥胖相关特征（体重指数[BMI]、腰臀比[WHR]以及经BMI调整后的腰臀比[WHRadjBMI]）与大脑皮质厚度之间的关系。
方法
利用在欧洲血统人群中进行的关于BMI（N = 806,834）、WHR（N = 697,734）、WHRadjBMI（N = 694,649）和大脑皮质厚度（N = 33,709）的大规模全基因组关联研究（GWAS）的汇总统计数据，我们进行了结合遗传相关性、多性状荟萃分析和孟德尔随机化分析的GWAS。
结果
我们的研究结果显示BMI与大脑皮质厚度之间存在很强的遗传相关性（rg = -0.0542，p = 0.0435），并且在WHR与大脑厚度之间也观察到了显著结果（rg = -0.0744，p = 0.009）。此外，我们在肥胖相关特征之间确定了三个基因座。孟德尔随机化分析支持BMI（逆方差加权[IVW]β = -0.006，95%置信区间 = -0.011至-3.85E-04；加权中位数β = -0.006，95%置信区间 = -0.013至-0.002）、WHR（IVWβ = -0.011，95%置信区间 = -0.018至-0.005；加权中位数β = -0.008，95%置信区间 = -0.018至-0.003）和WHRadjBMI（IVWβ = 0.011，95%置信区间 = -0.018至-0.005；加权中位数β = -0.008，95%置信区间 = -0.018至-0.002）在大脑皮质厚度方面的因果作用。
结论
本研究表明，基因预测的肥胖相关特征与皮质厚度降低存在因果关系。这些发现为肥胖与大脑结构变化之间的联系提供了遗传证据，并表明肥胖可能通过影响大脑结构，尤其是皮质厚度，与神经精神疾病相关。
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