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

Evangelia Stergiakouli,André G Uitterlinden,John P Kemp,George Davey Smith,Albert Hofman,David M Evans,Nicholas J Timpson,Fernando Rivadeneira,Ruth J Loos,Susan M Ring,Vincent W.V Jaddoe,Hendrik R Taal,Nina Balthasar,Jeremy M Tavaré,Tim J Cole,Romy Gaillard,Beate St Pourcain

doi:10.1002/oby.20840

Abstract

ObjectiveGenome-wide association studies (GWAS) of BMI are mostly undertaken under the assumption that “kg/m2” 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.MethodsA GWAS of height-adjusted BMI (BMI[x] = weight/heightx), 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.ResultsGWAS 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/m3.1 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/m2 (0.15, 0.35), P = 6 × 10−7)]. Results were replicated in an independent sample, the Generation R study.ConclusionsAnalysis 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.

Highlights

BMI (weight(kg)/height(m2)) has become a uniformly used measure of weight given height despite being defined in the 19th century based only on population specific knowledge at the time [1]
Different power terms [x] for height are required in the calculation of BMI in men and women and across different age groups and ethnicities to achieve maximum correlation with total body fat measured by Dual-energy X-ray absorptiometry (DXA) and minimum correlation with height
A similar effect was found for rs11676272 (0.20 kg/m3.1 change per allele G (0.13, 0.27), P 5 4 3 1029, MAF G 5 0.48), a nonsynonymous SNP located in the first exon of adenylate cyclase 3 (ADCY3) resulting in a serine-to-proline substitution in the second transmembrane helix of the expressed protein

Summary

Introduction

BMI (weight(kg)/height(m2)) has become a uniformly used measure of weight given height despite being defined in the 19th century based only on population specific knowledge at the time [1]. As an index of weight for height it ought to be uncorrelated with height, but in practice it is not. This complicates its biological interpretation as the correlation between BMI and height varies across different age groups, body types and ethnicities [2,3]. Different power terms [x] for height are required in the calculation of BMI in men and women and across different age groups and ethnicities to achieve maximum correlation with total body fat measured by Dual-energy X-ray absorptiometry (DXA) and minimum correlation with height

Methods

Results

Discussion

Conclusion