Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China.
Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China; The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China; School of Medicine, South China University of Technology, Guangzhou 510006, China.
EBioMedicine. 2023 Jul;93:104647. doi: 10.1016/j.ebiom.2023.104647. Epub 2023 Jun 8.
Observational studies have associated obesity with an increased risk of multiple sclerosis (MS). However, the role of genetic factors in their comorbidity remains largely unknown. Our study aimed to investigate the shared genetic architecture underlying obesity and MS.
By leveraging data from genome-wide association studies, we investigated the genetic correlation of body mass index (BMI) and MS by linkage disequilibrium score regression and genetic covariance analyser. The casualty was identified by bidirectional Mendelian randomisation. Linkage disequilibrium score regression in specifically expressed genes and multimarker analysis of GenoMic annotation was utilised to explore single-nucleotide polymorphism (SNP) enrichment at the tissue and cell-type levels. Shared risk SNPs were derived using cross-trait meta-analyses and Heritability Estimation from Summary Statistics. We explored the potential functional genes using summary-data-based Mendelian randomization (SMR). The expression profiles of the risk gene in tissues were further examined.
We found a significantly positive genetic correlation between BMI and MS, and the causal association of BMI with MS was supported (β = 0.22, P = 8.03E-05). Cross-trait analysis yielded 39 shared risk SNPs, and the risk gene GGNBP2 was consistently identified in SMR. We observed tissue-specific level SNP heritability enrichment for BMI mainly in brain tissues for MS in immune-related tissues, and cell-type-specific level SNP heritability enrichment in 12 different immune cell types in brain, spleen, lung, and whole blood. The expressions of GGNBP2 were significantly altered in the tissues of patients with obesity or MS compared to those of control subjects.
Our study indicates the genetic correlation and shared risk genes between obesity and MS. These findings provide insights into the potential mechanisms behind their comorbidity and the future development of therapeutics.
This work was funded by the National Natural Science Foundation of China (82171698, 82170561, 81300279, and 81741067), the Program for High-level Foreign Expert Introduction of China (G2022030047L), the Natural Science Foundation for Distinguished Young Scholars of Guangdong Province (2021B1515020003), Natural Science Foundation of Guangdong Province (2022A1515012081), the Foreign Distinguished Teacher Program of Guangdong Science and Technology Department (KD0120220129), the Climbing Programme of Introduced Talents and High-level Hospital Construction Project of Guangdong Provincial People's Hospital (DFJH201803, KJ012019099, KJ012021143, and KY012021183), and in part by VA Clinical Merit and ASGE clinical research funds (FWL).
观察性研究表明肥胖与多发性硬化症（MS）的风险增加有关。然而，遗传因素在它们的共病中的作用在很大程度上仍然未知。我们的研究旨在调查肥胖和 MS 共同存在的遗传结构。
通过利用全基因组关联研究的数据，我们通过连锁不平衡评分回归和遗传协方差分析器研究了体重指数（BMI）和 MS 的遗传相关性。通过双向孟德尔随机化确定因果关系。在特定表达基因中使用连锁不平衡评分回归和 GenoMic 注释的多标记分析，探索组织和细胞类型水平的单核苷酸多态性（SNP）富集。使用跨特征荟萃分析和基于汇总统计信息的遗传力估计来确定共享风险 SNP。我们使用基于汇总数据的孟德尔随机化（SMR）来探索潜在的功能基因。进一步检查了风险基因在组织中的表达谱。
我们发现 BMI 和 MS 之间存在显著的正遗传相关性，并且支持 BMI 与 MS 的因果关系（β=0.22，P=8.03E-05）。跨特征分析产生了 39 个共享风险 SNP，并且在 SMR 中一致鉴定出风险基因 GGNBP2。我们观察到 BMI 的组织特异性水平 SNP 遗传力在脑组织中主要富集，而 MS 的免疫相关组织中 SNP 遗传力富集，在脑、脾、肺和全血中的 12 种不同免疫细胞类型中 SNP 遗传力富集。与对照组相比，肥胖或 MS 患者的组织中 GGNBP2 的表达明显改变。
我们的研究表明肥胖和 MS 之间存在遗传相关性和共享风险基因。这些发现为它们的共病背后的潜在机制以及未来治疗方法的发展提供了见解。
这项工作得到了中国国家自然科学基金（82171698、82170561、81300279 和 81741067）、中国外国专家引进计划（G2022030047L）、广东省杰出青年自然科学基金（2021B1515020003）、广东省自然科学基金（2022A1515012081）、广东省科技厅外国杰出教师计划（KD0120220129）、广东省人民医院人才引进计划和高水平医院建设项目（FWL）、VA 临床功绩和 ASGE 临床研究基金（FWL）的部分资助。
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