甲状腺功能障碍与骨质疏松症的因果关系:双向两样本孟德尔随机化研究

Thyroid dysfunction and osteoporosis:a bidirectional,two-sample Mendelian randomization study

目的通过双向两样本孟德尔随机化(Mendelian randomization,MR)分析探索甲状腺功能障碍与骨质疏松症之间潜在的因果关系,为两者发病风险关联提供遗传学证据支持,并为早期防治骨质疏松症提供参考。方法根据全基因组关联研究中甲状腺功能减退(n=410141)、甲状腺功能亢进(n=460499)、桥本甲状腺炎(n=395640)和骨质疏松症(n=212778)的数据估计因果关系。以逆方差加权法为主要分析方法,以其他4种方法为补充分析方法,评估甲状腺功能障碍与骨质疏松症的因果效应。结果逆方差加权法结果显示,甲状腺功能减退[比值比(odds ratio,OR)=1.097,95%置信区间(confidence interval,CI)(1.017,1.183),P=0.017]、甲状腺功能亢进[OR=1.089,95%CI(1.000,1.186),P=0.049]、桥本甲状腺炎[OR=1.190,95%CI(1.054,1.343),P=0.005]对骨质疏松症因果效应均呈正相关。而反向MR分析结果不支持骨质疏松症会增加甲状腺功能减退、甲状腺功能亢进及桥本甲状腺炎的发病风险(P>0.05)。正向和反向MR分析的Cochran Q检验无异质性,MR-Egger截距测试结果表明不存在水平多效性,留一法分析结果显示MR分析结果可靠。结论甲状腺功能减退、甲状腺功能亢进、桥本甲状腺炎会增加骨质疏松症的风险,而在反向研究中并未发现骨质疏松症可增加甲状腺功能障碍的发病风险。

Objective To explore the potential causal relationship between thyroid dysfunction and osteoporosis(OP)through bidirectional two-sample Mendelian randomization(MR)analysis to provide genetic evidence for the risk association between thyroid dysfunction and OP,and provide reference for early prevention and treatment of OP.Methods Causal relationships were estimated based on data from genome-wide association studies for hypothyroidism(n=410141),hyperthyroidism(n=460499),Hashimoto thyroiditis(n=395640),and OP(n=212778).The inverse variance weighted method was used as the main analysis method,and the other four methods were used as the supplementary analysis methods to evaluate the causal effect of thyroid dysfunction and OP.Results The results of inverse variance weighted method showed that hypothyroidism[odds ratio(OR)=1.097,95%confidence interval(CI)(1.017,1.183),P=0.017],hyperthyroidism[OR=1.089,95%CI(1.000,1.186),P=0.049]and Hashimoto thyroiditis[OR=1.190,95%CI(1.054,1.343),P=0.005]were positively correlated with the causal effect of OP.The results of reverse MR analysis did not support that OP would increase the risk of hypothyroidism,hyperthyroidism or Hashimoto thyroiditis(P>0.05).In the bidirectional MR analyses,there was no heterogeneity in Cochran Q detection,MR-Egger intercept test results showed that there was no horizontal pleotropy,and the leave-one-out method analysis results showed that the MR analysis results were reliable.Conclusion Hypothyroidism,hyperthyroidism,and Hashimoto thyroiditis increase the risk of OP,while OP is not found to increase the risk of thyroid dysfunction in reverse studies.