As our understanding of genetics and the human genome continues to grow, so too does the realization that for study data to be meaningful and have an impact on public health, study cohorts need to be large and as ethnically diverse as the population. Support of this notion continues to roll in, as evidence from various studies utilizing these parameters has revealed exciting data that was not seen in more previous, more ethnically limited trials. A recent example, for instance, comes from an international team of researchers led by investigators at the Children’s Hospital of Philadelphia (CHOP), who analyzed data across multiple ethnicities and has produced the largest genetic study to date associated with common childhood obesity.
The Early Growth Genetics (EGG) Consortium discovered a robust new signal, fine-mapped previously reported genetic variants, and added to evidence that genetic influences on obesity operate across the lifespan. Findings from the new study were published recently in Human Molecular Genetics through an article titled “A Trans-ancestral Meta-Analysis of Genome-Wide Association Studies Reveals Loci Associated with Childhood Obesity.”
“As we continue to deepen our research into the genetics of obesity, this knowledge is bringing us closer to pinpointing specific causal genes and how they function in giving rise to obesity,” explained senior study investigator Struan Grant, PhD, director of the Center for Spatial and Functional Genomics (CSFG) at CHOP. “That detailed knowledge will help guide researchers toward developing more effective treatments.”
In recent years, obesity has increasingly received public attention due to its detrimental impact on public health and its rising prevalence of the condition among children—now higher than 20% in the United States. Obese adolescents tend to have a higher risk of mortality as adults. Although environmental factors, such as food choices and sedentary habits, contribute to rising rates of obesity in childhood, scientists have found strong evidence of genetic influences as well.
The current research extends the work of a 2012 collaborative study, also led by Grant, that identified genetic variants linked to common childhood obesity. That study, also from the EGG Consortium, was a meta-analysis focused on children of European ancestry only.
In this current work, the EGG Consortium scientists performed a meta-analysis of 30 genome-wide association studies comprising 13,000 cases and 15,600 controls, all from individuals of European, African, North and South American, and East Asian ancestry. A replication study then covered a subset of samples of 1,888 cases and 4,689 controls from European and North/South American cohorts.
“Searching for additional genetic variants associated with childhood obesity, we performed a trans-ancestral meta-analysis of thirty studies consisting of up to 13,005 cases (≥95th percentile of BMI achieved 2–18 years old) and 15,599 controls (consistently <50th percentile of BMI) of European, African, North/South American, and East Asian ancestry,” the authors wrote. “Suggestive loci were taken forward for replication in a sample of 1,888 cases and 4,689 controls from seven cohorts of European and North/South American ancestry. In addition to observing 18 previously implicated BMI or obesity loci, for both early and late-onset, we uncovered one completely novel locus in this trans-ancestral analysis (nearest gene: METTL15). The variant was nominally associated in only the European subgroup analysis but had a consistent direction of effect in other ethnicities.”
The scientists found a strong, novel variant associated with childhood obesity, closest to the METTL15 gene, and confirmed 18 variants previously linked to childhood obesity or body mass index (BMI). The team also used fine-mapping analyses to narrow down potential causal variants at four different locations to fewer than 10 specific single-base changes (single-nucleotide polymorphisms, or SNPs).
“Obesity is becoming such an alarming health problem in children that we need to scale up translational efforts to develop innovative therapies,” noted study co-investigator Hakon Hakonarson, MD, PhD, director of the Center for Applied Genomics (CAG) at CHOP and a long-term collaborator of Grant’s.
The genetic roots of obesity and BMI are very similar in both children and adults, and that future treatment may reflect those commonalities.
“Follow-up functional studies will be needed to connect potential causal variants with specific effector genes, to better understand the biology of obesity and offer insights into potential treatments,” Grant concluded.