Genome-wide association study of height-adjusted BMI in childhood identifies functional variant in ADCY3.

OBJECTIVE: Genome-wide association studies (GWAS) of BMI are mostly undertaken under the assumption that "kg/m(2) " is an index of weight fully adjusted for height, but in general this is not true. The aim here was to assess the contribution of common genetic variation to a adjusted version of that phenotype which appropriately accounts for covariation in height in children. METHODS: A GWAS of height-adjusted BMI (BMI[x] = weight/height(x) ), calculated to be uncorrelated with height, in 5809 participants (mean age 9.9 years) from the Avon Longitudinal Study of Parents and Children (ALSPAC) was performed. RESULTS: GWAS based on BMI[x] yielded marked differences in genomewide results profile. SNPs in ADCY3 (adenylate cyclase 3) were associated at genome-wide significance level (rs11676272 (0.28 kg/m(3.1) change per allele G (0.19, 0.38), P = 6 × 10(-9) ). In contrast, they showed marginal evidence of association with conventional BMI [rs11676272 (0.25 kg/m(2) (0.15, 0.35), P = 6 × 10(-7) )]. Results were replicated in an independent sample, the Generation R study. CONCLUSIONS: Analysis of BMI[x] showed differences to that of conventional BMI. The association signal at ADCY3 appeared to be driven by a missense variant and it was strongly correlated with expression of this gene. Our work highlights the importance of well understood phenotype use (and the danger of convention) in characterising genetic contributions to complex traits.

Small and large size for gestational age at birth, infant growth, and childhood overweight.

OBJECTIVE: The associations of size at birth, with infant growth of head circumference, length and weight, and fat mass and body mass index in preschool children were examined. DESIGN AND METHODS: In a population-based prospective cohort study among 3,941 children, head circumference, length and weight until the age of 4 years were repeatedly measured. Catch-up and catch-down growth were defined as a change in standard deviation scores of >0.67 from birth to 2 years of age. RESULTS: Although most children born small and large size for gestational age showed infant catch-up and catch-down growth, respectively, their mean head circumference, length and weight remained smaller and larger respectively, until the age of 4 years. Catch-up growth in children with a small and appropriate weight for gestational age and lack of catch-down growth in children born with a large weight for gestational age were associated with higher body mass index in preschool children. Children born with an appropriate weight for gestational age with catch-up growth and children born with a large weight for gestational without catch-down growth had increased risks of childhood overweight {odds ratios: 3.11 (95% confidence interval[95% CI] 2.37, 4.08) and 12.46 (95% CI: 6.07, 25.58) respectively}. CONCLUSIONS: Children born small, appropriate and large size for gestational age have different growth patterns in early childhood and persistent differences in their head circumference, length, and weight until the age of 4 years. Children born with an appropriate weight for gestational age with catch-up growth and large weight for gestational children without catch-down growth have an increased risk of overweight.

Genome-wide profiling of blood pressure in adults and children.

Hypertension is an important determinant of cardiovascular morbidity and mortality and has a substantial heritability, which is likely of polygenic origin. The aim of this study was to assess to what extent multiple common genetic variants contribute to blood pressure regulation in both adults and children and to assess overlap in variants between different age groups, using genome-wide profiling. Single nucleotide polymorphism sets were defined based on a meta-analysis of genome-wide association studies on systolic blood pressure and diastolic blood pressure performed by the Cohort for Heart and Aging Research in Genome Epidemiology (n=29 136), using different P value thresholds for selecting single nucleotide polymorphisms. Subsequently, genetic risk scores for systolic blood pressure and diastolic blood pressure were calculated in an independent adult population (n=2072) and a child population (n=1034). The explained variance of the genetic risk scores was evaluated using linear regression models, including sex, age, and body mass index. Genetic risk scores, including also many nongenome-wide significant single nucleotide polymorphisms, explained more of the variance than scores based only on very significant single nucleotide polymorphisms in adults and children. Genetic risk scores significantly explained ≤1.2% (P=9.6*10(-8)) of the variance in adult systolic blood pressure and 0.8% (P=0.004) in children. For diastolic blood pressure, the variance explained was similar in adults and children (1.7% [P=8.9*10(-10)] and 1.4% [P=3.3*10(-5)], respectively). These findings suggest the presence of many genetic loci with small effects on blood pressure regulation both in adults and children, indicating also a (partly) common polygenic regulation of blood pressure throughout different periods of life.