Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index

Abstract

A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores. We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 × 10(-8)) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 × 10(-10)) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index.

Commentary: Two-sample Mendelian randomization: opportunities and challenges

“…From the original papers it can be seen that the instrument for adult BMI is stronger than for the other traits (the respective R 2 for adult BMI, birthweight, child BMI and WHR, are: 0.027, 0.008, 0.020 and 0.013; the R 2 for child BMI is only for the three novel SNPs but, as the authors of the original paper point out, it was calculated on a relatively small sample and needs to be treated with some caution). 14 , 18–20 Interestingly, although Gao et al. use the most up-to-date BMI GWAS data, 20 they do not do the same for WHR, despite the most recent GWAS for WHR adjusted for BMI identifying 33 additional variants (as well as confirming the 14 used here from the earlier GWAS) and being published around the same time as the most up-to-date BMI GWAS.…”

The Omics of Obesity

“…Since these two studies, there has been a boom in GWAS studies and subsequent obesity susceptibility loci identified. To date, ~200 variants associated with obesity-related phenotypes have been identified; however, it is postulated that these loci only account for <10% of the variance [10][11][12][13][14][15]. Although this is quite low, and means that 90% of variance remains to be explained, they have provided us with an emerging wealth of knowledge of the genomic localisation, frequency and effect sizes, and potential functional implications that these loci may have.…”

The two sides of Faim2 -- modulation of cell death and regeneration

“…Protective effects of Faim2 in cultured neurons have also been described for Purkinje cells and cortical neurons 7,10 . In addition these neuronal effects, Faim2 single nucleotide polymorphisms (SNPs) have been linked to an increased susceptibility for obesity, especially in childhood, in a genome wide association study (GWAS) 11 . For certain subpopulations, i.e.…”