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

ABSTRACT: 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.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.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.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.

SUBMITTER: Stergiakouli E

PROVIDER: S-EPMC4265207 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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

Stergiakouli Evangelia E Gaillard Romy R Tavaré Jeremy M JM Balthasar Nina N Loos Ruth J RJ Taal Hendrik R HR Evans David M DM Rivadeneira Fernando F St Pourcain Beate B Uitterlinden André G AG Kemp John P JP Hofman Albert A Ring Susan M SM Cole Tim J TJ Jaddoe Vincent W V VW Davey Smith George G Timpson Nicholas J NJ

Obesity (Silver Spring, Md.) 20140721 10

<h4>Objective</h4>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.<h4>Methods</h4>A GWAS of height-adjusted BMI (BMI[x] = weight/height(x) ), calculated to be uncorrelated with heigh ...[more]

PMID: 25044758

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Project description:Autosomal recessive polycystic kidney disease (ARPKD) is characterized by bilateral fibrocystic changes resulting in pronounced kidney enlargement. Impairment of kidney function is highly variable and widely available prognostic markers are urgently needed as a base for clinical decision-making and future clinical trials. In this observational study we analyzed the longitudinal development of sonographic kidney measurements in a cohort of 456 ARPKD patients from the international registry study ARegPKD. We furthermore evaluated correlations of sonomorphometric findings and functional kidney disease with the aim to describe the natural disease course and to identify potential prognostic markers. Kidney pole-to-pole (PTP) length and estimated total kidney volume (eTKV) increase with growth throughout childhood and adolescence despite individual variability. Height-adjusted PTP length decreases over time, but such a trend cannot be seen for height-adjusted eTKV (haeTKV) where we even observed a slight mean linear increase of 4.5 ml/m per year during childhood and adolescence for the overall cohort. Patients with two null PKHD1 variants had larger first documented haeTKV values than children with missense variants (median (IQR) haeTKV 793 (450-1098) ml/m in Null/null, 403 (260-538) ml/m in Null/mis, 230 (169-357) ml/m in Mis/mis). In the overall cohort, estimated glomerular filtration rate decreases with increasing haeTKV (median (IQR) haeTKV 210 (150-267) ml/m in CKD stage 1, 472 (266-880) ml/m in stage 5 without kidney replacement therapy). Strikingly, there is a clear correlation between haeTKV in the first eighteen months of life and kidney survival in childhood and adolescence with ten-year kidney survival rates ranging from 20% in patients of the highest to 94% in the lowest quartile. Early childhood haeTKV may become an easily obtainable prognostic marker of kidney disease in ARPKD, e.g. for the identification of patients for clinical studies.

Dataset Information

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

Publications

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

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