Hong Xuanming, Cao Hui, Cao Weihua, Lv Jun, Yu Canqing, Huang Tao, Sun Dianjianyi, Liao Chunxiao, Pang Yuanjie, Hu Runhua, Gao Ruqin, Yu Min, Zhou Jinyi, Wu Xianping, Liu Yu, Yin Shengli, Gao Wenjing, Li Liming
Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, 100191, China.
Key Laboratory of Epidemiology of Major Diseases, Ministry of Education, Peking University, Beijing, 100191, China.
Cell Biosci. 2025 Jul 23;15(1):108. doi: 10.1186/s13578-025-01446-2.
Both obesity and DNA methylation (DNAm) are influenced by genetic factors. Despite more than a thousand of obesity-related DNAm sites (CpGs) being identified, studies that account for genetic influences in these associations are limited.
Using data from 1,074 twins in the Chinese National Twin Registry and bivariate structural equation models (SEMs), we investigated the phenotypic (Rph), genetic (Ra), and environmental (Re) correlations between genome-wide DNAm and three obesity indices: BMI, waist circumference (WC), and waist-to-hip ratio (WHR). Genome-wide, correlations between DNAm and obesity were small (Rph = 0.04, Ra = 0.08-0.09, Re = 0.02-0.03). For CpGs with high phenotypic correlation (Rph > 0.1), the mean genetic and environmental correlations were 0.23-0.24 and 0.03-0.05, respectively, indicating significant genetic influence on the DNAm-obesity associations. To further investigate the role of genetic influences, we then categorized the CpGs into different groups: high phenotypic correlation (Rph ≥ 0.2); high phenotypic and genetic correlations (Rph > 0.1 and Ra > 0.5); high phenotypic and low genetic correlations (Rph > 0.1 and Ra < 0.5). Association studies were conducted in the full population and in the monozygotic (MZ) twin-paired design, where genetic influences were controlled. For CpGs with Rph ≥ 0.2, 9, 8, and 22 were associated with BMI, WC, and WHR in the full population, but only 6, 1, and 1 CpGs remained significant after controlling for genetic effects in MZ twin-pair analyses. For CpGs with Rph > 0.1 and Ra > 0.5, genetic factors predominantly drove the association, and none of the 155/155/189 CpGs associated with BMI/WC/WHR in the full population were significant in MZ-paired analyses. For CpGs with Rph > 0.1 and Ra < 0.1, genetic effects were minimal or confounding, with 89, 4, and 17 significant in both full population and MZ-paired analyses.
Our results highlight the significant genetic influences on the DNAm-obesity relationships, which may explain the low replicability of obesity-related DNAm markers. This indicates that genetic influences should be carefully considered in DNAm-related studies.
肥胖和DNA甲基化（DNAm）均受遗传因素影响。尽管已鉴定出一千多个与肥胖相关的DNAm位点（CpG），但考虑这些关联中遗传影响的研究却很有限。
利用中国国家双胞胎登记处1074对双胞胎的数据和双变量结构方程模型（SEM），我们研究了全基因组DNAm与三个肥胖指标之间的表型（Rph）、遗传（Ra）和环境（Re）相关性，这三个肥胖指标分别是体重指数（BMI）、腰围（WC）和腰臀比（WHR）。在全基因组范围内，DNAm与肥胖之间的相关性较小（Rph = 0.04，Ra = 0.08 - 0.09，Re = 0.02 - 0.03）。对于表型相关性高（Rph > 0.1）的CpG，平均遗传和环境相关性分别为0.23 - 0.24和0.03 - 0.05，表明遗传因素对DNAm - 肥胖关联有显著影响。为了进一步研究遗传影响的作用，我们随后将CpG分为不同组：高表型相关性（Rph≥0.2）；高表型和遗传相关性（Rph > 0.1且Ra > 0.5）；高表型和低遗传相关性（Rph > 0.1且Ra < 0.5）。在全人群和同卵双胞胎（MZ）配对设计中进行了关联研究，其中遗传影响得到了控制。对于Rph≥0.2的CpG，在全人群中有9个、8个和22个分别与BMI、WC和WHR相关，但在MZ双胞胎配对分析中控制遗传效应后，只有6个、1个和1个CpG仍然显著。对于Rph > 0.1且Ra > 0.5的CpG，遗传因素主要驱动了这种关联，在全人群中与BMI/WC/WHR相关的155/155/189个CpG在MZ配对分析中均无显著意义。对于Rph > 0.1且Ra < 0.1的CpG，遗传效应最小或存在混杂因素，在全人群和MZ配对分析中分别有89个、4个和17个显著相关。
我们的结果突出了遗传因素对DNAm - 肥胖关系的显著影响，这可能解释了与肥胖相关的DNAm标记物可重复性低的原因。这表明在与DNAm相关的研究中应仔细考虑遗传影响。
