association studies have revealed many genetic loci associated with BMI or adiposity in adults. However, the genetic loci underlying BMI in children are less well known. The biological background of BMI may differ between children and adults. In addition, it may be that the relative contributions of the same genetic loci differ depending on age, for example due to different geneenvironment interactions or body fat distributions. A limited number of loci have been identified to associate with dichotomous definitions of childhood obesity. Also, the roles of specific known adult loci for BMI, such as FTO and ADCY3, have been described in children. The age-specific effects are illustrated by longitudinal studies on the effects of the well-known adult BMI increasing risk allele of FTO with BMI throughout childhood. It has been reported that the adult BMI increasing risk allele is associated with lower BMI in infancy, an earlier adiposity rebound and a higher BMI from the age of 5 years onwards. To date, studies did not present a large GWAS metaanalysis on the full spectrum of childhood BMI. To identify genetic loci influencing childhood BMI, we metaanalyzed 20 GWAS with a total of 35 668 children of European ancestry, combining data for around 2.5 million single-nucleotide polymorphisms imputed to the HapMap imputation panel. We used as outcome sex- and age-adjusted standard deviation scores at the oldest age between 2 and 10 years. replication and joint analyses for the 43 genome-wide and suggestive loci. In total, 15 of these reached genome-wide significance in the joint analysis. Twelve out of these 15 had been reported previously for related phenotypes. SNPs in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 are associated with adult BMI or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, BMI increased 0.04 Standard Deviation Score , 0.05 SDS and 0.14 SDS for rs13253111, rs8092503 and rs13387838, respectively. Genetic risk score We combined the 15 identified genome-wide significant SNPs into a genetic risk score that summed the number of BMIincreasing alleles weighted by their betas from the discovery analysis and rescaled to a range of 0 to 30, which is the maximum number of risk alleles. The risk score was associated with childhood BMI in 1955 children from the PIAMA Study, one of our largest replication cohorts. For each additional average risk allele in the score, childhood BMI increased by 0.073 SDS . This risk score explained PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19822663 2.0% of the variance in childhood BMI. Associations with adult body mass index and childhood obesity The genetic correlation between childhood BMI and adult BMI was 0.73. A lookup of the 15 SNPs associated with childhood BMI in a recently published GWAS meta-analysis on adult BMI in >300 000 Crenolanib participants revealed that all SNPs showed evidence for association with adult BMI, with P-values of 0.005, 5.76 10-5 and 0.003 for the novel SNPs rs13253111, rs8092503 and rs13387838, respectively. Also, the direction of the effect estimates for all 15 SNPs was the same in children and adults . The 15 SNPs found in this study explained 0.94% of the variance in adult BMI in the GIANT consortium. A reverse lookup in our dataset of the 97 known genome-wide significant loci previously reported to be associated with adult BMI showed that 22 out of the 97 loci were significant
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