Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index.

Genome-wide association results for the BMI meta-analysis(a) Manhattan plot showing the significance of association between all SNPs and BMI in the stage 1 meta-analysis, highlighting SNPs previously reported to show genome-wide significant association with BMI (blue), weight or waist circumference (green), and the 18 new regions described here (red). The 19 SNPs that reached genome-wide significance at Stage 1 (13 previously reported and 6 new) are listed in Table 1). (b) Quantile-quantile (Q-Q) plot of SNPs in stage 1 meta-analysis (black) and after removing any SNPs within 1 Mb of the 10 previously reported genome-wide significant hits for BMI (blue), after additionally excluding SNPs from the four loci for waist/weight (green) and after excluding SNPs from all 32 confirmed loci (red). The plot was abridged at the Y-axis (at P < 10−20) to better visualise the excess of small P-values after excluding the 32 confirmed loci (Supplementary Fig. 3 shows full-scale Q-Q plot). The shaded region is the 95% concentration band. (c) Plot of effect size (in inverse normally transformed units (invBMI)) versus effect allele frequency of newly identified and previously identified BMI variants after stage 1 + stage 2 analysis; including the 10 previously identified BMI loci (blue), the four previously identified waist and weight loci (green) and the 18 newly identified BMI loci (blue). The dotted lines represent the minimum effect sizes that could be identified for a given effect-allele frequency with 80% (upper line), 50% (middle line), and 10% (lower line) power, assuming a sample size of 123,000 individuals and a α-level of 5×10−8.

Combined impact of risk alleles on BMI/obesity(a) Combined effect of risk alleles on average BMI in the population-based Atherosclerosis Risk in Communities (ARIC) study (n = 8,120 individuals of European descent). For each individual, the number of “best guess” replicated (n = 32) risk alleles from imputed data (0,1,2) per SNP was weighted for their relative effect sizes estimated from the stage 2 data. Weighted risk alleles were summed for each individual and the overall individual sum was rounded to the nearest integer to represent the individual’s risk allele score (range 16–44). Along the x-axis, individuals in each risk allele category are shown (grouped ≤21 and ≥38 at the extremes), and the mean BMI (+/− SEM) is plotted (y axis on right), with the line representing the regression of the mean BMI values across the risk-allele scores. The histogram (y-axis on left) represents the number of individuals in each risk-score category. (b) The area under the ROC curve (AUC) of two different models predicting the risk of obesity (BMI = ≥30 kg/m2) in the n = 8,120 genotyped individuals of European descent in the ARIC Study. Model 1, represented by the solid line, includes age, age2, and sex (AUC = 0.515, P = 0.023 for difference from AUCnull = 0.50). Model 2, represented by the dashed line, includes age, age2, sex, and the n = 32 confirmed BMI SNPs (AUC = 0.0575, P < 10−5 for difference from AUCnull = 0.50). The difference between both AUCs is significant (P < 10−4).

Regional plots of selected replicating BMI loci with missense and CNV variantsSNPs are plotted by position on chromosome against association with BMI (−log10 P-value). The SNP name shown on the plot was the most significant SNP after stage 1 meta-analysis. Estimated recombination rates (from HapMap) are plotted in cyan to reflect the local LD structure. The SNPs surrounding the most significant SNP are color-coded to reflect their LD with this SNP (taken from pairwise r2 values from the HapMap CEU database, www.hapmap.org). Genes, position of exons, and direction of transcription from UCSC genome browser (http://genome.ucsc.edu) are noted. Hashmarks represent SNP positions available in the meta-analysis. (a, b, c) Missense variants noted with their amino acid change for the gene noted above the plot. (d) Structural haplotypes and BMI association signal in the GPRC5B region. A 21 kb deletion polymorphism is associated with 4 SNPs (r2=1.0) that comprise the best haplogroup associating with BMI. Plots were generated using LocusZoom (http://csg.sph.umich.edu/locuszoom).

Phenotypic variance explained by common variants(a) Variance explained is higher when SNPs not reaching genome-wide significance are included in the prediction model. The y-axis represents the proportion of variance explained at different P-value thresholds from stage 1 meta-analysis. Results are given for three studies (RSII, RSIII, QIMR), which were not included in the meta-analysis, after exclusion of all samples from The Netherlands (for RSII and RSIII) and the United Kingdom (for QIMR) from the discovery analysis for this sub-analysis. The dotted line represents the weighted average of the explained variance of three validation sets. (b) Cumulative number of susceptibility loci expected to be discovered, including those we have already identified and others that have yet to be detected, by the expected percentage of phenotypic variation explained and sample size required for a one-stage GWA study assuming a GC correction is utilized. The projections are based on loci that achieved a significance level of P < 5×10−8 in the joint analysis of stage 1 and stage 2 and the distribution of their effect sizes in stage 2. The dotted red line corresponds to the expected phenotypic variance explained by the 22 loci that are expected to be discovered in a one-stage GWAS with the sample size of stage 1 of this study.

Second signal at the MC4R locus contributing to BMISNPs are plotted by position in a 1 Mb window of chromosome 18 against association with BMI ( log10 P-value). Panel (a) highlights the most significant SNP in stage 1 meta-analysis, panel (b) the most significant SNP after conditional analysis where the model included the most strongly associated SNP from panel A as a covariate. Estimated recombination rates (from HapMap) are plotted in cyan to reflect the local LD structure. The SNPs surrounding the most significant SNP are color-coded to reflect their LD with this SNP (taken from pairwise r2 values from the HapMap CEU database, www.hapmap.org). Genes, exons, and direction of transcription from UCSC genome browser (genome.ucsc.edu) are noted. Hashmarks at the top of the figure represent positions of SNPs in the meta-analysis. Regional plots were generated using LocusZoom (http://csg.sph.umich.edu/locuszoom).