Genetic predisposition to high BMI and changes in BMI during adolescence modulate associations between adult BMI and plasma molecules involved in glucose metabolism

Introduction Glucose metabolism and related blood molecules are strongly associated with adult body mass index (BMI). However, it is unclear whether the magnitude of these associations differs in people whose BMI increased rapidly during adolescence or who have a genetic predisposition to high BMI.

The analyses included 373 Finnish participants (39% males) with BMI data at approximate ages 11.5, 14, 17.5, 22, and 37 years. BMI trajectories (defined as BMI changes (i.e. slope) and BMI baseline (i.e. intercept)) were calculated during adolescence (from 11.5 to 17.5 years of age) using linear mixed-effects (LME) models and adulthood (from ∼22 to 37 years of age). We employed LME models to quantify the associations between BMI trajectories during adulthood and nine plasma molecules related to glucose metabolism measured at age ∼22 years. For significant associations, we tested whether the levels of the molecules interacted with either changes in BMI during adolescence or a Polygenic Risk Score (PRS) of BMI (PRSBMI). Stratified analyses were performed for men and women.

During adulthood, BMI changes per year were 0.16 kg/m2 in men and 0.17 kg/m2 in women. The analysis revealed seven statistically significant associations between plasma molecules with adult BMI, but no associations with weight change during adulthood. Four statistically significant interactions with plasma molecules were identified, all of which were found in women. In predicting BMI at ∼22 years old, BMI changes in adolescence interacted positively with glucose (p=2.0e-04) and negatively with citrate levels (p= 5.6e-04), and the PRSBMI interacted positively with glucose (p= 3.4e-04) and negatively with citrate (p= 8.3e-03).

The current study provides evidence that PRSBMI and BMI changes during adolescence modulate the associations between BMI during adulthood with glucose and citrate blood levels in women. Competing Interest Statement The authors have declared no competing interest. Funding Statement Funding: Phenotype and omics data collection in FinnTwin12 cohort has been supported by the Wellcome Trust Sanger Institute, the Broad Institute, ENGAGE (European Network for Genetic and Genomic Epidemiology), FP7-HEALTH-F4-2007, grant agreement number 201413, National Institute of Alcohol Abuse and Alcoholism (grants AA-12502, AA-00145, and AA-09203 to RJ Rose and AA15416 and K02AA018755 to DM Dick, and R01AA015416 to J Salvatore), the Academy of Finland (grants 100499, 205585, 118555, 141054, 264146, 308248 to JK, and grants 328685, 307339, 297908 and 251316 to M Ollikainen, and the Centre of Excellence in Complex Disease Genetics grants 312073, 336823, and 352792 to JK), and Sigrid Juselius Foundation (to MO). This research was partly funded by the European Union Horizon 2020 research and innovation program under grant agreement No 874724 (Equal-Life). Equal-Life is part of the European Human Exposome Network. KS and JK have been supported by the European Union Horizon Europe Research and Innovation programme under Grant Agreement number 101080117. Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union. Neither the European Union nor the granting authority can be held responsible for them. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Ethics Committee of the Helsinki University Central Hospital District (HUS) approved the most recent data collection (wave 5) (HUS/2226/2021, dated September 22, 2021) as well as the use of previously collected data. The participants or their parents/legal guardians provided informed consent when participating in the surveys. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability Statement The FT12 data is not publicly available due to the restrictions of informed consent. However, the FT12 data is available through the Institute for Molecular Medicine Finland (FIMM) Data Access Committee (DAC) (fimmdac{at}helsinki.fi) for authorised researchers who have IRB/ethics approval and an institutionally approved study plan. To ensure the protection of privacy and compliance with national data protection legislation, a data use/transfer agreement is needed, the content and specific clauses of which will depend on the nature of the requested data.