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Causal role of high body mass index in multiple chronic diseases: a systematic review and meta-analysis of Mendelian randomization studies.

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BACKGROUND: Obesity is a worldwide epidemic that has been associated with a plurality of diseases in observational studies. The aim of this study was to summarize the evidence from Mendelian randomization (MR) studies of the association between body mass index (BMI) and chronic diseases. METHODS: PubMed and Embase were searched for MR studies on adult BMI in relation to major chronic diseases, including diabetes mellitus; diseases of the circulatory, respiratory, digestive, musculoskeletal, and nervous systems; and neoplasms. A meta-analysis was performed for each disease by using results from published MR studies and corresponding de novo analyses based on summary-level genetic data from the FinnGen consortium (n = 218,792 individuals). RESULTS: In a meta-analysis of results from published MR studies and de novo analyses of the FinnGen consortium, genetically predicted higher BMI was associated with increased risk of type 2 diabetes mellitus, 14 circulatory disease outcomes, asthma, chronic obstructive pulmonary disease, five digestive system diseases, three musculoskeletal system diseases, and multiple sclerosis as well as cancers of the digestive system (six cancer sites), uterus, kidney, and bladder. In contrast, genetically predicted higher adult BMI was associated with a decreased risk of Dupuytren's disease, osteoporosis, and breast, prostate, and non-melanoma cancer, and not associated with Alzheimer's disease, amyotrophic lateral sclerosis, or Parkinson's disease. CONCLUSIONS: The totality of the evidence from MR studies supports a causal role of excess adiposity in a plurality of chronic diseases. Hence, continued efforts to reduce the prevalence of overweight and obesity are a major public health goal.



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Springer Science and Business Media LLC
Wellcome Trust (204623/Z/16/Z)
This work was supported by research grants from the Swedish Research Council (Vetenskapsrådet; 2016-01042 and 2019-00977), the Swedish Research Council for Health, Working Life and Welfare (Forte; 2018-00123), and the Swedish Heart-Lung Foundation (Hjärt-Lungfonden; 20190247). Stephen Burgess is supported by Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (204623/Z/16/Z). Open Access funding provided by Karolinska Institute.