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

Stergiakouli E, Gaillard R, Tavaré JM, Balthasar N, Loos RJ, Taal HR, Evans DM, Rivadeneira F, St Pourcain B, Uitterlinden AG, Kemp JP, Hofman A, Ring SM, Cole TJ, Jaddoe VW, Davey Smith G, Timpson NJ - Obesity (Silver Spring) (2014)

Bottom Line: 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) ).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.

View Article: PubMed Central - PubMed

Affiliation: MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.

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Regional plots in ADCY3(adenylate cyclase 3) locus showing that the association at the locus is attributed to rs11676272. (a) BMI adjusted for height, age and sex in ALSPAC, (b) BMI adjusted for height, age and sex conditioning on rs11676272 in ALSPAC. Each circle represents a SNP plotted by its position on the chromosome against its association (−log10 P). The SNPs are colored according to their linkage disequilibrium (LD) with rs11676272 using pairwise r2 values from HapMap CEU samples. The diagram in light blue represents the LD structure in the region. Data for gene structure from UCSC Genome Browser are shown below the diagram. Plots were generated using LocusZoom 22 [Avon Longitudinal Study of Parents and Children (ALSPAC)].
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fig03: Regional plots in ADCY3(adenylate cyclase 3) locus showing that the association at the locus is attributed to rs11676272. (a) BMI adjusted for height, age and sex in ALSPAC, (b) BMI adjusted for height, age and sex conditioning on rs11676272 in ALSPAC. Each circle represents a SNP plotted by its position on the chromosome against its association (−log10 P). The SNPs are colored according to their linkage disequilibrium (LD) with rs11676272 using pairwise r2 values from HapMap CEU samples. The diagram in light blue represents the LD structure in the region. Data for gene structure from UCSC Genome Browser are shown below the diagram. Plots were generated using LocusZoom 22 [Avon Longitudinal Study of Parents and Children (ALSPAC)].

Mentions: For variation at SNPs across the ADCY3 locus and conventional BMI there was not genome-wide significant evidence for association (Figure 2b) [rs11676272 (0.25 kg/m2 (0.15, 0.35), P = 6 × 10−7)]. zBMI (BMI standardised for age) was not associated with rs11676272 [0.022 change in zBMI per allele G (−0.01 to 0.06), P = 0.224)]. In contrast, the association of rs1558902 in FTO remained genome-wide significant [0.33 kg/m2 (0.23, 0.43), P = 1 × 10−10]. Evidence for association at the ADCY3 locus and rs11676272 [0.28 kg/m2 (0.19, 0.38), P = 6 × 10−9] remained genome-wide significant, as expected, when performing a GWAS on conventional BMI adjusted for height (Figure 2c). Furthermore, in sensitivity analyses performing regional single marker association analyses with BMI adjusted for height conditional on rs11676272 dose, all evidence for association across the ADCY3 region was lost (Figure 3).


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

Stergiakouli E, Gaillard R, Tavaré JM, Balthasar N, Loos RJ, Taal HR, Evans DM, Rivadeneira F, St Pourcain B, Uitterlinden AG, Kemp JP, Hofman A, Ring SM, Cole TJ, Jaddoe VW, Davey Smith G, Timpson NJ - Obesity (Silver Spring) (2014)

Regional plots in ADCY3(adenylate cyclase 3) locus showing that the association at the locus is attributed to rs11676272. (a) BMI adjusted for height, age and sex in ALSPAC, (b) BMI adjusted for height, age and sex conditioning on rs11676272 in ALSPAC. Each circle represents a SNP plotted by its position on the chromosome against its association (−log10 P). The SNPs are colored according to their linkage disequilibrium (LD) with rs11676272 using pairwise r2 values from HapMap CEU samples. The diagram in light blue represents the LD structure in the region. Data for gene structure from UCSC Genome Browser are shown below the diagram. Plots were generated using LocusZoom 22 [Avon Longitudinal Study of Parents and Children (ALSPAC)].
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4265207&req=5

fig03: Regional plots in ADCY3(adenylate cyclase 3) locus showing that the association at the locus is attributed to rs11676272. (a) BMI adjusted for height, age and sex in ALSPAC, (b) BMI adjusted for height, age and sex conditioning on rs11676272 in ALSPAC. Each circle represents a SNP plotted by its position on the chromosome against its association (−log10 P). The SNPs are colored according to their linkage disequilibrium (LD) with rs11676272 using pairwise r2 values from HapMap CEU samples. The diagram in light blue represents the LD structure in the region. Data for gene structure from UCSC Genome Browser are shown below the diagram. Plots were generated using LocusZoom 22 [Avon Longitudinal Study of Parents and Children (ALSPAC)].
Mentions: For variation at SNPs across the ADCY3 locus and conventional BMI there was not genome-wide significant evidence for association (Figure 2b) [rs11676272 (0.25 kg/m2 (0.15, 0.35), P = 6 × 10−7)]. zBMI (BMI standardised for age) was not associated with rs11676272 [0.022 change in zBMI per allele G (−0.01 to 0.06), P = 0.224)]. In contrast, the association of rs1558902 in FTO remained genome-wide significant [0.33 kg/m2 (0.23, 0.43), P = 1 × 10−10]. Evidence for association at the ADCY3 locus and rs11676272 [0.28 kg/m2 (0.19, 0.38), P = 6 × 10−9] remained genome-wide significant, as expected, when performing a GWAS on conventional BMI adjusted for height (Figure 2c). Furthermore, in sensitivity analyses performing regional single marker association analyses with BMI adjusted for height conditional on rs11676272 dose, all evidence for association across the ADCY3 region was lost (Figure 3).

Bottom Line: 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) ).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.

View Article: PubMed Central - PubMed

Affiliation: MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.

Show MeSH