Sequence variants associated with BMI affect disease risk through BMI itself

• Published in: Nature communications Vol. 15; no. 1; pp. 9335 - 9
• Main Authors: Einarsson, Gudmundur, Thorleifsson, Gudmar, Steinthorsdottir, Valgerdur, Zink, Florian, Helgason, Hannes, Olafsdottir, Thorhildur, Rognvaldsson, Solvi, Tragante, Vinicius, Ulfarsson, Magnus O., Sveinbjornsson, Gardar, Snaebjarnarson, Audunn S., Einarsson, Hafsteinn, Aegisdottir, Hildur M., Jonsdottir, Gudrun A., Helgadottir, Anna, Gretarsdottir, Solveig, Styrkarsdottir, Unnur, Arnason, Hannes K., Bjarnason, Ragnar, Sigurdsson, Emil, Arnar, David O., Bjornsson, Einar S., Palsson, Runolfur, Bjornsdottir, Gyda, Stefansson, Hreinn, Thorgeirsson, Thorgeir, Sulem, Patrick, Thorsteinsdottir, Unnur, Holm, Hilma, Gudbjartsson, Daniel F., Stefansson, Kari
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.11.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 631/208/205; 631/208/457; 692/499; Adult; Aged; Attenuation; Body Mass Index; Cerebral infarction; Congestive heart failure; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - epidemiology; Diabetes Mellitus, Type 2 - genetics; Disease; Disease control; Error analysis; Fatty liver; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Glucose Intolerance - genetics; Glucose tolerance; Health risk assessment; Health risks; Heart attacks; Humanities and Social Sciences; Humans; Iceland - epidemiology; Kidney diseases; Liver diseases; Male; Mendelian Randomization Analysis; Middle Aged; multidisciplinary; Myocardial infarction; Myocardial Infarction - epidemiology; Myocardial Infarction - genetics; Obesity - complications; Obesity - epidemiology; Obesity - genetics; Pleiotropy; Polymorphism, Single Nucleotide; Residual effects; Risk; Risk Factors; Science; Science (multidisciplinary); United Kingdom - epidemiology; Upper bounds; United Kingdom; Iceland
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-53568-9

Mendelian Randomization studies indicate that BMI contributes to various diseases, but it’s unclear if this is entirely mediated by BMI itself. This study examines whether disease risk from BMI-associated sequence variants is mediated through BMI or other mechanisms, using data from Iceland and the UK Biobank. The associations of BMI genetic risk score with diseases like fatty liver disease, knee replacement, and glucose intolerance were fully attenuated when conditioned on BMI, and largely for type 2 diabetes, heart failure, myocardial infarction, atrial fibrillation, and hip replacement. Similar attenuation was observed for chronic kidney disease and stroke, though results varied. Findings were consistent across sexes, except for myocardial infarction. Residual effects may result from temporal BMI changes, pleiotropy, measurement error, non-linear relationships, non-collapsibility, or confounding. The attenuation extent of BMI genetic risk score on disease associations suggests the potential impact of reducing BMI on disease risk. BMI contributes to various diseases, but it was unclear whether the risk was mediated by BMI itself. Here, the authors demonstrate that BMI mediates most of this risk, and suggest an upper bound on disease risk that can be mitigated by lowering BMI.