New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Comparison between parameters from maximal cycle ergometer test first without respiratory gas analysis and thereafter with respiratory gas analysis among healthy prepubertal children

It is important to distinguish true and clinically relevant changes and methodological noise from measure to measure. In the clinical practice maximal cycle ergometer tests are typically performed first without respiratory gas analysis, and thereafter, if needed, with respiratory gas analysis. Therefore we report comparison of parameters from maximal cycle ergometer exercise tests which were done first without respiratory gas analysis and thereafter with it in 38 prepubertal and healthy children (20 girls, 18 boys). The Bland-Altman method was used to assess agreement in maximal workload (WMAX) and heart rate (HR) and systolic blood pressure (SBP) between rest and maximum. Girls achieved higher WMAX in the exercise tests with respiratory gas analysis compared with exercise tests without respiratory gas analysis (P=0.016), whereas WMAX was similar in the tests among boys. Maximal HR (proportional offset -1%; CV% 3.3) and highest SBP (proportional offset 3%; CV% 10.6) were similar in the tests among children. Precision and agreement for HR improved and precision for SBP worsened with increasing exercise intensity. Heteroscedasticity was not observed for WMAX, HR or SBP. We conclude that maximal cycle ergometer tests without and with respiratory gas analysis can be used consecutively because measurement of respiratory gases did not impair performance or have significant effect on the maximality of the exercise tests. Our results suggest that similar references can be used for children who accept or refuse using a mask during maximal exercise test.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Trans-Ethnic Fine-Mapping of Lipid Loci Identifies Population-Specific Signals and Allelic Heterogeneity That Increases the Trait Variance Explained

Genome-wide association studies (GWAS) have identified ~ 100 loci associated with blood lipid levels, but much of the trait heritability remains unexplained, and at most loci the identities of the trait-influencing variants remain unknown. We conducted a trans-ethnic fine-mapping study at 18, 22, and 18 GWAS loci on the Metabochip for their association with triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), respectively, in individuals of African American (n = 6,832), East Asian (n = 9,449), and European (n = 10,829) ancestry. We aimed to identify the variants with strongest association at each locus, identify additional and population-specific signals, refine association signals, and assess the relative significance of previously described functional variants. Among the 58 loci, 33 exhibited evidence of association at P,161024 in at least one ancestry group. Sequential conditional analyses revealed that ten, nine, and four loci in African Americans, Europeans, and East Asians, respectively, exhibited two or more signals. At these loci, accounting for all signals led to a 1.3- to 1.8-fold increase in the explained phenotypic variance compared to the strongest signals. Distinct signals across ancestry groups were identified at PCSK9 and APOA5. Trans-ethnic analyses narrowed the signals to smaller sets of variants at GCKR, PPP1R3B, ABO, LCAT, and ABCA1. Of 27 variants reported previously to have functional effects, 74% exhibited the strongest association at the respective signal. In conclusion, trans-ethnic highdensity genotyping and analysis confirm the presence of allelic heterogeneity, allow the identification of population-specific variants, and limit the number of candidate SNPs for functional studies

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

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

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

Discovery and refinement of loci associated with lipid levels

<p>Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P <5 x 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.</p>