Finding the missing heritability in pediatric obesity: the contribution of genome-wide complex trait analysis.

ABSTRACT

Known single-nucleotide polymorphisms (SNPs) explain <2% of the variation in body mass index (BMI) despite the evidence of >50% heritability from twin and family studies, a phenomenon termed 'missing heritability'. Using DNA alone for unrelated individuals, a novel method (in a software package called Genome-wide Complex Trait Analysis, GCTA) estimates the total additive genetic influence due to common SNPs on whole-genome arrays. GCTA has made major inroads into explaining the 'missing heritability' of BMI in adults. This study provides the first GCTA estimate of genetic influence on adiposity in children. Participants were from the Twins Early Development Study (TEDS), a British twin birth cohort. BMI s.d. scores (BMI-SDS) were obtained from validated parent-reported anthropometric measures when children were about 10 years old (mean=9.9; s.d.=0.84). Selecting one child per family (n=2269), GCTA results from 1.7 million DNA markers were used to quantify the additive genetic influence of common SNPs. For direct comparison, a standard twin analysis in the same families estimated the additive genetic influence as 82% (95% CI 0.74-0.88, P<0.001). GCTA explained 30% of the variance in BMI-SDS (95% CI 0.02-0.59; P=0.02). These results indicate that 37% of the twin-estimated heritability (30/82%) can be explained by additive effects of multiple common SNPs, and provide compelling evidence for strong genetic influence on adiposity in childhood.