A trans-ancestral meta-analysis of genome-wide association studies reveals loci associated with childhood obesity

Abstract

Although hundreds of genome-wide association studies-implicated loci have been reported for adult obesity-related traits, less is known about the genetics specific for early-onset obesity and with only a few studies conducted in non-European populations to date. Searching for additional genetic variants associated with childhood obesity, we performed a trans-ancestral meta-analysis of 30 studies consisting of up to 13 005 cases (≥95th percentile of body mass index (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. Suggestive loci were taken forward for replication in a sample of 1888 cases and 4689 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 with only the European subgroup analysis but had a consistent direction of effect in other ethnicities. We then utilized trans-ancestral Bayesian analysis to narrow down the location of the probable causal variant at each genome-wide significant signal. Of all the fine-mapped loci, we were able to narrow down the causative variant at four known loci to fewer than 10 single nucleotide polymorphisms (SNPs) (FAIM2, GNPDA2, MC4R and SEC16B loci). In conclusion, an ethnically diverse setting has enabled us to both identify an additional pediatric obesity locus and further fine-map existing loci.

Analysis of Polymorphisms rs7093069-IL-2RA, rs7138803-FAIM2, and rs1748033-PADI4 in the Group of Adolescents With Autoimmune Thyroid Diseases

“…Many studies suggest that the polymorphism of this gene is associated with obesity and the development of type 2 diabetes (14). A multicenter study of more than 13,000 children aged 2-18 with BMI above 95 percentile years confirmed the occurrence of this gene polymorphism in obese children (15). The variant of gene FAIM2-rs7138803 is associated with BMI z-scores in children over 6 years (16).…”

“…It can play a role in cerebellum development. The polymorphism of the molecular coding gene is associated with giant obesity and diabetes mellitus type 2 and increases the risk of cardiovascular diseases (14)(15)(16)(17)(18)(19).…”

Pleiotropic genetic influence on birth weight and childhood obesity

“…In contrast, for three loci ( EBF1 , NCOA1 and SEC16B) , nearly all alleles associated with decreased birth weight were associated with higher CBMI/COB risk (Table S4 – S5 ). Furthermore, we evaluated our findings using the European-ancestry summary statistics in a recent childhood obesity GWAS 46 . Out of the 342 SNPs in our study found to be associated with both birthweight and childhood obesity, 98.5% reached > 95% posterior probability when we used this validation childhood obesity GWAS (Table S6 ).…”

The human mitochondrial 12S rRNA m4C methyltransferase METTL15 is required for proper mitochondrial function

“…Importantly, a reduction in the oxidative capacity of brown adipocytes results in impaired thermogenesis, and has been linked to diet-induced obesity (33) . In this context, it’s important to note that microdeletion and SNPs in METTL15 gene are highly associated with obesity (16, 17) . Therefore, we speculate that if altered METTL15 activity impacst obesity onset, it’s likely to be due to the ability of METTL5 to regulate mitochondrial functions by methylating 12S mt-rRNA.…”

“…Intriguingly, the microdeletion region always encompasses a METTL-famlily protein METTL15. More recently, a trans-ancestral meta-analysis of genome-wide association studies uncovered a completely novel single nucleotide polymorphism (SNP) (rs10835310) at METTL15 associated with childhood obesity, ( 17 ), further implicating the involvement of METTL15 in this human syndrome, although the underlying molecular mechanisms for these associations is still unclear.…”