Distinct Genetic Profiles Influence Body Mass Index Between Infancy and Adolescence

Body mass index (BMI) changes throughout life with age-varying genetic contributions. We aimed to investigate the genetic contribution to BMI across early life using repeated measures from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Random regression modelling was used to estimate the genetic covariance matrix ( Kg ) of BMI trajectories from ages one to 18 years with 65,930 repeated BMI measurements from 6,291 genotyped ALSPAC participants. The Kg matrix was used to estimate SNP-based heritability ( hSNP2 ) at yearly intervals from 1-18 years and genetic correlations across early life. We also performed an eigenvalue decomposition of Kg to identify age-varying genetic patterns of BMI. Finally, we investigated the impact of a polygenic score derived from adult BMI on the estimated genetic components across early life. The hSNP2 was relatively constant across early life, between 23-30%. The genetic contribution to BMI in early childhood is different to that in later childhood, indicated by the diminishing strength of genetic correlation across different ages. The eigenvalue decomposition revealed that the primary axis of variation (explaining 89% of the genetic variance in Kg ) increases with age from zero and reaches a plateau in adolescence, while the second eigenfunction (explaining around 9% of Kg ) represents factors with opposing effects on BMI between early and later ages. Adjusting for the adult BMI polygenic score attenuated the hSNP2 from late childhood; for example, hSNP2 is 29.8% (SE=6.5%) at 18 years of age and attenuates to 14.5% (SE=6.3%) after adjusting for the adult BMI polygenic score. Although common genetic variation explains around 23-30% of BMI variability across early life, our findings indicate that there is a different genetic profile operating during infancy compared to later childhood and adolescence. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement G.W. and N.M.W. are funded by a National Health and Medical Research Council (Australia) Investigator grant (APP2008723). K.E.K. was supported by the Australian Research Council (grant FL180100072). The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. GWAS data in ALSPAC was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. A comprehensive list of funding provided to ALSPC from grants is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). This research was specifically funded by Wellcome Trust and MRC (core), 076467/Z/05/Z. ### 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 Avon Longitudinal Study of Parents and Children Ethics and Law Committee and the Local Research Ethics Committees gave ethical approval for this work. The Institutional Human Research Ethics Committee of the University of Queensland gave ethical approval for this work. 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 The Avon Longitudinal Study of Parents and Children cohort can be applied for by submitting a request to the Data Access Committee. Requirements for data access are described at http://www.bristol.ac.uk/alspac/.