Lipid loci with multiple signals in Europeans.

a<p>LD (<i>r</i>²/D′) with SNP showing the strongest evidence of association at each locus.</p>b<p>β: effect size from an additive model and corresponding to the effect allele, in the unit of mmol/L for HDL-C, LDL-C and natural log transformed TG.</p>c<p><i>P</i> values of sequential conditional analyses, in which we added the SNP with the strongest evidence of association into the regression model as a covariate and tested for the next strongest SNP until the strongest SNP showed a conditional <i>P</i> value>10⁻⁴ and had no annotation suggesting potential function.</p>d<p>Variance explained by SNPs at each locus was estimated based on European samples.</p>e<p><i>P</i> values of initial association in African Americans and East Asians.</p

Trans-ethnic fine-mapping narrowed the association signals.

a<p><i>P</i> meta: <i>P</i> values from meta-analysis combining samples of African American, East Asian and European ancestries.</p>b<p>Direction: effect direction of each individual studies in the order of ARIC, MEC, WHI batch1, WHI batch2, HyperGEN, CLHNS, TAICHI, Finnish T2D, Finnish unaffected, Norwegian T2D and Norwegian unaffected.</p>c<p><i>P</i> het: <i>P</i> values for heterogeneity, indicating whether observed effect sizes are homogeneous across ancestry samples.</p>d<p><i>I</i>²: index of the degree of heterogeneity.</p

Reported functional variants exhibited the strongest association at a signal (<i>P</i><10⁻⁴).

*<p>AA, African American; EUR, European; ASN, East Asian.</p

Trans-ethnic high-density genotyping narrows the association signal at the HDL-C locus <i>PPP1R3B</i>.

<p>Association in Europeans (A), East Asians (B), African Americans (C) and in a combined trans-ethnic meta-analysis (D). Index SNP rs6601299 colored in purple is the variant showing strongest evidence of association in the combined trans-ethnic meta-analysis.</p

LDL-C locus <i>PCSK9</i> exhibited seven signals in African Americans.

<p>Initial association in the main analysis (A). Residual association in sequential conditional analysis by sequentially adding the lead SNPs into the regression model (B–G). Each SNP was colored according to its LD (<i>r²</i>) in the PAGE consortium, with the strongest SNP colored in purple and symbols designating genomic annotation defined in the ‘annotation key’. Genomic coordinates refer to build 36 (hg18).</p

Lipid loci with multiple signals in East Asians.

a<p>LD (<i>r</i>²/D′) with SNP showing the strongest evidence of association at each locus.</p>b<p>β: effect size from an additive model and corresponding to the effect allele, in the unit of mmol/L for HDL-C, LDL-C and natural log transformed TG.</p>c<p><i>P</i> values of sequential conditional analyses, in which we added the SNP with the strongest evidence of association into the regression model as a covariate and tested for the next strongest SNP until the strongest SNP showed a conditional <i>P</i> value>10⁻⁴ and had no annotation suggesting potential function.</p>d<p>Variance explained by SNPs at each locus was estimated based on CLHNS samples (n = 1,716).</p>e<p><i>P</i> values of initial association in African Americans and Europeans.</p

Novel loci achieving genome-wide significance (P<5x10^-8) in meta-analyses for PA-adjusted SNP main effect (P_adjPA) or the joint test of SNP main effect and SNP-PA interaction (P_joint).

<p>Novel loci achieving genome-wide significance (P<5x10^-8) in meta-analyses for PA-adjusted SNP main effect (P_adjPA) or the joint test of SNP main effect and SNP-PA interaction (P_joint).</p

Genes of biological interest within 500 kb of lead SNPs associated with WC_adjBMI or WHR_adjBMI.

<p>Genes of biological interest within 500 kb of lead SNPs associated with WC_adjBMI or WHR_adjBMI.</p

Genes of biological interest within 500 kb of lead SNPs associated with BMI.

<p>Genes of biological interest within 500 kb of lead SNPs associated with BMI.</p

Power to identify PA-adjusted main, joint or GxPA interaction effects in 200,000 individuals (45,000 inactive, 155,000 active).

<p>The plots compare power to identify genome-wide significant main effects (P_adjPA<5x10^-8, dashed black), joint effects (P_JOINT<5x10^-8, dotted green) or GxPA interaction effects (P_INT<5x10^-8, solid magenta) as well as the power to identify Bonferroni-corrected interaction effects (P_INT<0.05/number of loci, solid orange) for the SNPs that reached a genome-wide significant PA-adjusted main effect association (P_adjPA<5x10^-8). The power computations were based on analytical power formulae provided elsewhere [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1006528#pgen.1006528.ref050" target="_blank">50</a>] and were conducted a-priori based on various types of known realistic BMI effect sizes [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1006528#pgen.1006528.ref051" target="_blank">51</a>]. <b>Panels A, C, E</b>: Assuming an effect in inactive individuals similar to a small (, comparable to the known BMI effect of the <i>NUDT3</i> locus), medium (, comparable to the known BMI effect of the <i>BDNF</i> locus) and large (, comparable to the known BMI effect of the <i>FTO</i> locus) realistic effect on BMI and for various effects in physically active individuals (varied on the x axis); <b>Panels B,D,F</b>: Assuming an effect in physically active individuals similar to the small, medium and large realistic effects of the <i>NUDT3</i>, <i>BDNF and FTO</i> loci on BMI and for various effects in inactive individuals (varied on x axis).</p