American Diabetes Association
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The Effect of General Adiposity and Central Body Fat Distribution on the Circulating Metabolome: a Multi-Cohort Non-Targeted Metabolomics Observational and Mendelian Randomization Study

Version 2 2021-12-07, 15:03
Version 1 2021-11-17, 13:58
posted on 2021-12-07, 15:03 authored by Shafqat Ahmad, Ulf Hammar, Beatrice Kennedy, Samira Salihovic, Andrea Ganna, Lars Lind, Johan Sundström, Johan Ärnlöv, Christian Berne, Ulf Risérus, Patrik KE Magnusson, Susanna C Larsson, Tove Fall
Obesity is associated with adverse health outcomes, but the metabolic effects have not yet been fully elucidated. We aimed to investigate the association between adiposity with circulating metabolites and to address causality with Mendelian randomization (MR). Metabolomics data was generated by non-targeted ultra-performance liquid-chromatography coupled to time-of-flight mass-spectrometry in plasma and serum from three population-based Swedish cohorts: ULSAM (N=1,135), PIVUS (N=970), and TwinGene (N=2,059). We assessed associations between general adiposity measured as body mass index (BMI) and central body fat distribution measured as waist-to-hip ratio adjusted for BMI (WHRadjBMI) with 210 annotated metabolites. We employed MR analysis to assess causal effects. Lastly, we attempted to replicate the MR findings in the KORA and TwinsUK cohorts (N=7,373), the CHARGE consortium (N=8,631), the Framingham Heart Study (N=2,076) and the DIRECT consortium (N=3,029). BMI was associated with 77 metabolites, while WHRadjBMI was associated with 11 and 3 metabolites in women and men, respectively. The MR analyses in the Swedish cohorts suggested a causal association (p-value <0.05) of increased general adiposity and reduced levels of arachidonic acid, dodecanedioic acid and lysophosphatidylcholine (P-16:0) as well as with increased creatine levels. The replication effort provided support for a causal association of adiposity on reduced levels of arachidonic acid (p-value 0.03). Adiposity is associated with variation of large parts of the circulating metabolome, however causality needs further investigation in well-powered cohorts.


European Association for the Study of Diabetes Göran Gustafssons Stiftelse för Naturvetenskaplig och Medicinsk Forskning European Commission > Horizon 2020 Framework Programme > H2020 Excellent Science > H2020 European Research Council GUTSY – 801965 Hjärt-Lungfonden 20170988 Royal Society of Arts and Scientists Sweden x Svenska Forskningsrådet Formas 2020-00989 Vetenskapsrådet 2015–03477 2017-00641 2018-02784