Sequence variants associated with BMI affect disease risk through BMI itself

Gudmundur Einarsson, Gudmar Thorleifsson, Valgerdur Steinthorsdottir, Florian Zink, Hannes Helgason, Thorhildur Olafsdottir, Solvi Rognvaldsson, Vinicius Tragante, Magnus O. Ulfarsson, Gardar Sveinbjornsson, Audunn S. Snaebjarnarson, Hafsteinn Einarsson, Hildur M. Aegisdottir, Gudrun A. Jonsdottir, Anna Helgadottir, Solveig Gretarsdottir, Unnur Styrkarsdottir, Hannes K. Arnason, Ragnar Bjarnason, Emil Sigurdsson, David O. Arnar, Einar S. Bjornsson, Runolfur Palsson, Gyda Bjornsdottir, Hreinn Stefansson, Thorgeir Thorgeirsson, Patrick Sulem, Unnur Thorsteinsdottir, Hilma Holm, Daniel F. Gudbjartsson and Kari Stefansson ()
Additional contact information
Gudmundur Einarsson: Inc.
Gudmar Thorleifsson: Inc.
Valgerdur Steinthorsdottir: Inc.
Florian Zink: Inc.
Hannes Helgason: Inc.
Thorhildur Olafsdottir: Inc.
Solvi Rognvaldsson: Inc.
Vinicius Tragante: Inc.
Magnus O. Ulfarsson: Inc.
Gardar Sveinbjornsson: Inc.
Audunn S. Snaebjarnarson: Inc.
Hafsteinn Einarsson: Inc.
Hildur M. Aegisdottir: Inc.
Gudrun A. Jonsdottir: Inc.
Anna Helgadottir: Inc.
Solveig Gretarsdottir: Inc.
Unnur Styrkarsdottir: Inc.
Hannes K. Arnason: Inc.
Ragnar Bjarnason: University of Iceland
Emil Sigurdsson: Development Centre for Primary Health Care in Iceland
David O. Arnar: Inc.
Einar S. Bjornsson: University of Iceland
Runolfur Palsson: University of Iceland
Gyda Bjornsdottir: Inc.
Hreinn Stefansson: Inc.
Thorgeir Thorgeirsson: Inc.
Patrick Sulem: Inc.
Unnur Thorsteinsdottir: Inc.
Hilma Holm: Inc.
Daniel F. Gudbjartsson: Inc.
Kari Stefansson: Inc.

Nature Communications, 2024, vol. 15, issue 1, 1-9

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-53568-9

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