Trans-ancestry genome-wide association study of childhood body mass index identifies novel loci and age-specific effects

Over the past 30 years, obesity prevalence has markedly increased globally, including among children. Although genome-wide association studies (GWASs) have identified over 1,000 genetic loci associated with obesity-related traits in adults, the genetic architecture of childhood obesity is less well characterized. Moreover, most childhood obesity GWASs have been restricted to severely obese children, in relatively small sample sizes, and in primarily European-ancestry populations. To identify genetic loci associated with early-childhood body mass index (BMI), we performed GWAS of BMI Z scores in eight ancestrally diverse cohorts: ZOE 2.0 cohort, the Santiago Longitudinal Study (SLS), the Vanderbilt University BioVU biobank, the Geisinger MyCode Health Initiative biobank, Study of Latino (SOL) Youth, Pelotas (Brazil) Birth Cohort, Cameron County Hispanic Cohort (CCHC), and Viva La Familia cohort. We subsequently performed inverse-variance-weighted fixed-effect meta-analysis of these results with previously published GWAS summary statistics of BMI Z scores of children in the Early Growth Genetics (EGG) Consortium and the Norwegian Mother and Child Cohort (MoBa), constituting a final total of 84,804 individuals. We identified 39 genome-wide significant loci associated with childhood BMI, including three putatively novel loci (EFNA5 and DTWD2, RP11-2N5.1 on chromosome 5, and LSM14A on chromosome 19). We also observed a dynamic nature of genetic loci-BMI associations across the life course, with distinct effects across childhood and adulthood, highlighting possible critical periods for early-childhood interventions. These findings strengthen calls for larger population-based studies of children across age strata and across diverse populations.