Joint models reveal genetic architecture of transitions between pubertal stages and their association with BMI in a Latino population

Early or late pubertal onset can lead to disease in adulthood, including cancer, obesity, type 2 diabetes, metabolic disorders, bone fractures and psychopathologies. Thus, knowing the age at which puberty is attained is crucial as it can serve as a risk factor for future diseases. Pubertal development is divided into five stages of sexual maturation in boys and girls according to the standardized Tanner scale. We performed genome-wide association studies (GWAS) on the GOCS cohort composed of admixed children with European and Native American ancestry. Using joint models that integrate time-to-event survival parameters and longitudinal trajectories of body-mass index (BMI), we identified genetic variants associated with phenotypic transitions between pairs of Tanner stages. We identified 43 novel significant associations, most of them in boys. The GWAS on Tanner 3 → 4 transition in boys captured an association peak around the growth-related genes LARS2 and LIMD1 genes, the former of which causes ovarian dysfunction when mutated. The associated variants are expression– and splicing Quantitative Trait Loci regulating gene expression and alternative splicing in multiple tissues. Further, higher individual Native American genetic ancestry proportions predicted a significantly earlier arrival to Tanner 2 stage in boys but not in girls. Finally, the joint models identified longitudinal BMI parameters significantly associated in several Tanner stages’ transitions, confirming the association of BMI on pubertal timing. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the Fondo Nacional de Ciencia y Tecnología (FONDECYT) [1200146 to S.E., L.V. and E.B.; 1190346 to V.M.]. S.E., and L.V. were additionally supported by the Instituto Milenio de Investigación Sobre los Fundamentos de los Datos (IMFD). D.A. was supported by the UKRI Medical Research Council, grant number MC UU 00002/5. ### 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: This study was approved by the Scientific Ethics Committees of Instituto de Nutrición y Tecnología en Alimentos (INTA) and Pontificia Universidad Católica de Chile. 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 genetic data used in this study are from adolescents, many of which are less than 18 years old. Thus, we are not allowed to publish or share their raw data. The summary statistics of this study can be found in the NHGRI-EBI GWAS Catalog server, under the code GCP000453.