Xunying Zhao, Lin He, Xueyao Wu, Li Zhang, Jinyu Xiao, Changfeng Xiao, Yang Qu, Jingwei Zhu, Chenjiarui Qin, Deqin Huang, Pengyue Shen, Tao Han, Mengyu Fan, Jiayuan Li, Stephen Burgess, Xia Jiang
{"title":"解开身体质量指数和骨密度之间关联的不同因果途径：一项全面的孟德尔随机化研究。","authors":"Xunying Zhao, Lin He, Xueyao Wu, Li Zhang, Jinyu Xiao, Changfeng Xiao, Yang Qu, Jingwei Zhu, Chenjiarui Qin, Deqin Huang, Pengyue Shen, Tao Han, Mengyu Fan, Jiayuan Li, Stephen Burgess, Xia Jiang","doi":"10.1186/s12916-025-04139-2","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>While the protective role of body mass index (BMI) in bone mass has been well-documented, the divergent associations between BMI and estimated bone mineral density (eBMD), attributed to its highly heterogeneous nature, remain insufficiently understood.</p><p><strong>Methods: </strong>Leveraging the hitherto largest genome-wide summary statistics, we conducted a two-sample Mendelian randomization (MR) to re-evaluate the effect of genetically predicted BMI on eBMD. Then, MR-Clust was applied to examine the potential presence of distinct causal pathways underlying the BMI-eBMD link. Utilizing tissue-partitioned MR, we estimated the distinct effects of separated tissue-specific subcomponents of BMI on eBMD, further supplemented by multivariable MR of body composition phenotypes on eBMD.</p><p><strong>Results: </strong>We reconfirmed the significant positive association between genetically predicted BMI and eBMD (β<sub>IVW</sub> = 0.13, P value = 1.28 × 10<sup>-34</sup>). Potential distinct causal pathways contributing to the observed total effect were identified by MR-Clust, with some exerting a protective effect while others leading to its deterioration. Tissue-partitioned MR suggested a marginally independent protective association between skeletal muscle-tissue instrumented BMI and eBMD (β<sub>IVW</sub> = 0.14, P value = 4.98 × 10<sup>-2</sup>) after accounting for adipose-tissue instrumented BMI, which was supported by the independent association between genetically predicted lean mass and eBMD after accounting for other body composition phenotypes.</p><p><strong>Conclusions: </strong>Our results shed preliminary insights into the intricate relationship between obesity and bone mass, highlighting divergent causal pathways underlying the association between BMI and eBMD. Our findings emphasize the potential importance of precision obesity management over merely a general indicator as BMI in future public health strategies for osteoporosis prevention.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"23 1","pages":"305"},"PeriodicalIF":7.0000,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12121138/pdf/","citationCount":"0","resultStr":"{\"title\":\"Disentangling the divergent causal pathways underlying the association between body mass index and bone mineral density: a comprehensive Mendelian randomization study.\",\"authors\":\"Xunying Zhao, Lin He, Xueyao Wu, Li Zhang, Jinyu Xiao, Changfeng Xiao, Yang Qu, Jingwei Zhu, Chenjiarui Qin, Deqin Huang, Pengyue Shen, Tao Han, Mengyu Fan, Jiayuan Li, Stephen Burgess, Xia Jiang\",\"doi\":\"10.1186/s12916-025-04139-2\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>While the protective role of body mass index (BMI) in bone mass has been well-documented, the divergent associations between BMI and estimated bone mineral density (eBMD), attributed to its highly heterogeneous nature, remain insufficiently understood.</p><p><strong>Methods: </strong>Leveraging the hitherto largest genome-wide summary statistics, we conducted a two-sample Mendelian randomization (MR) to re-evaluate the effect of genetically predicted BMI on eBMD. Then, MR-Clust was applied to examine the potential presence of distinct causal pathways underlying the BMI-eBMD link. Utilizing tissue-partitioned MR, we estimated the distinct effects of separated tissue-specific subcomponents of BMI on eBMD, further supplemented by multivariable MR of body composition phenotypes on eBMD.</p><p><strong>Results: </strong>We reconfirmed the significant positive association between genetically predicted BMI and eBMD (β<sub>IVW</sub> = 0.13, P value = 1.28 × 10<sup>-34</sup>). Potential distinct causal pathways contributing to the observed total effect were identified by MR-Clust, with some exerting a protective effect while others leading to its deterioration. Tissue-partitioned MR suggested a marginally independent protective association between skeletal muscle-tissue instrumented BMI and eBMD (β<sub>IVW</sub> = 0.14, P value = 4.98 × 10<sup>-2</sup>) after accounting for adipose-tissue instrumented BMI, which was supported by the independent association between genetically predicted lean mass and eBMD after accounting for other body composition phenotypes.</p><p><strong>Conclusions: </strong>Our results shed preliminary insights into the intricate relationship between obesity and bone mass, highlighting divergent causal pathways underlying the association between BMI and eBMD. Our findings emphasize the potential importance of precision obesity management over merely a general indicator as BMI in future public health strategies for osteoporosis prevention.</p>\",\"PeriodicalId\":9188,\"journal\":{\"name\":\"BMC Medicine\",\"volume\":\"23 1\",\"pages\":\"305\"},\"PeriodicalIF\":7.0000,\"publicationDate\":\"2025-05-28\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12121138/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"BMC Medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1186/s12916-025-04139-2\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, GENERAL & INTERNAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"BMC Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s12916-025-04139-2","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, GENERAL & INTERNAL","Score":null,"Total":0}
Disentangling the divergent causal pathways underlying the association between body mass index and bone mineral density: a comprehensive Mendelian randomization study.
Background: While the protective role of body mass index (BMI) in bone mass has been well-documented, the divergent associations between BMI and estimated bone mineral density (eBMD), attributed to its highly heterogeneous nature, remain insufficiently understood.
Methods: Leveraging the hitherto largest genome-wide summary statistics, we conducted a two-sample Mendelian randomization (MR) to re-evaluate the effect of genetically predicted BMI on eBMD. Then, MR-Clust was applied to examine the potential presence of distinct causal pathways underlying the BMI-eBMD link. Utilizing tissue-partitioned MR, we estimated the distinct effects of separated tissue-specific subcomponents of BMI on eBMD, further supplemented by multivariable MR of body composition phenotypes on eBMD.
Results: We reconfirmed the significant positive association between genetically predicted BMI and eBMD (βIVW = 0.13, P value = 1.28 × 10-34). Potential distinct causal pathways contributing to the observed total effect were identified by MR-Clust, with some exerting a protective effect while others leading to its deterioration. Tissue-partitioned MR suggested a marginally independent protective association between skeletal muscle-tissue instrumented BMI and eBMD (βIVW = 0.14, P value = 4.98 × 10-2) after accounting for adipose-tissue instrumented BMI, which was supported by the independent association between genetically predicted lean mass and eBMD after accounting for other body composition phenotypes.
Conclusions: Our results shed preliminary insights into the intricate relationship between obesity and bone mass, highlighting divergent causal pathways underlying the association between BMI and eBMD. Our findings emphasize the potential importance of precision obesity management over merely a general indicator as BMI in future public health strategies for osteoporosis prevention.
期刊介绍：
BMC Medicine is an open access, transparent peer-reviewed general medical journal. It is the flagship journal of the BMC series and publishes outstanding and influential research in various areas including clinical practice, translational medicine, medical and health advances, public health, global health, policy, and general topics of interest to the biomedical and sociomedical professional communities. In addition to research articles, the journal also publishes stimulating debates, reviews, unique forum articles, and concise tutorials. All articles published in BMC Medicine are included in various databases such as Biological Abstracts, BIOSIS, CAS, Citebase, Current contents, DOAJ, Embase, MEDLINE, PubMed, Science Citation Index Expanded, OAIster, SCImago, Scopus, SOCOLAR, and Zetoc.
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