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

Genome-Wide Significant SNPs from the Sex-Combined Multi-Ethnic Meta-Analysis.

<p>The novel loci identified using Multi-Ethnic Meta-analysis (that were not identified in the European only analysis) are listed in <b>bold</b>.</p>*<p>When possible, plausible biological candidate genes have been listed; otherwise, the closest gene is designated.</p>‡<p>Lead SNP is the SNP with the lowest <i>p</i>-value for each locus.</p>†<p>Positions are relative to Human Genome NCBI Build 36.</p>§<p>log₁₀ Bayes factor (BF) from the MANTRA analysis. A log₁₀ BF of 6 and higher was considered as a conservative threshold for genome-wide significance.</p>††<p>The posterior probability of heterogeneity between studies.</p>¶<p>EA: effect allele, NEA: non-effect allele.</p>¶¶<p>EAF: Frequency of effect allele in CEU, East Asian, and AA, populations respectively.</p

Regional plots of eight newly discovered genome-wide significant chromosomal regions associated with adiponectin concentrations in European populations.

<p>A) chromosome 16q23.2, B) chromosome 19 q13.11 C) Chromosome 3p21.1, D) two loci on chromosome 12q24.31, E) chromosome 8q24.13, F) chromosome 6p21.1, and G) chromosome 1q41. In each panel, purple diamonds indicate the top SNPs, which have the strongest evidence of association. Each circle shows a SNP with a color scale relating the r² value for that SNP and the top SNP from HapMap CEU. Blue lines indicate estimated recombination rates from HapMap. The bottom panels illustrate the relative position of genes near each locus. Candidate genes are indicated by red ovals.</p

The Association of Lead Genome-Wide Significant SNPs for Adiponectin with mRNA Levels of Their Nearest Gene.

‡<p>Lead SNP is the SNP with the lowest <i>p</i>-value for each gene in gene expression data.</p>‡‡<p>Lead SNP is the SNP with the lowest <i>p</i>-value for each locus in meta-analysis from discovery phase.</p>¶<p>EA: Effect allele.</p>¶¶<p>EAF: Frequency of effect allele.</p>§<p>Betas are estimated expression levels of the genes.</p>*<p>P value for lead SNP is the SNP in gene expression data.</p>**<p>P value for lead SNP in meta-analysis from discovery phase.</p>$<p>r² LD between lead SNP from expression and lead SNP from meta-analysis.</p

The Association of mRNA Levels from Genes in Candidate Loci in Human Adipocytes with Circulating Adiponectin Levels.

§<p>Betas are estimated from log transformed and quantile-quantile normalized values.</p>*<p>These two loci are independent loci.</p

Lead SNP per Locus for Genome-Wide Significant SNPs Arising from the Sex-Combined Meta-Analysis in European Populations.

<p> <i>All SNPs achieving genome-wide significance in the joint analysis phase are marked in italics.</i></p>*<p>Joint analysis indicates results from the meta-analysis of discovery and follow-up <i>in-silico</i> and <i>de-novo</i> phases.</p>**<p>When possible, plausible biological candidate genes have been listed; otherwise, the closest gene is designated.</p>‡<p>Lead SNP is the SNP with the lowest <i>p</i>-value for each locus.</p>§<p>Betas are estimated from models using the natural log transformed adiponectin.</p>¶<p>EA: Effect allele, NEA: Non-effect allele.</p>¶¶<p>EAF: Effect allele frequency.</p

Manhattan plots for meta-analyses in the discovery phase.

<p>A) Combined sex analysis in European populations, B) Meta-Analysis of Multiple Ethnicities. The Manhattan plots show −Log₁₀ (<i>p</i>-value) measures for association between single nucleotide polymorphisms (SNPs) and chromosomal position. The SNPs that achieved genome-wide significance are highlighted in green.</p

Flow chart of study design.

<p>Flow chart of study design.</p

Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: A multi-ethnic meta-analysis of 45,891 individuals

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10−8- 1.2 ×10−43). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10−4). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10−3, n = 22,044), increased triglycerides (p = 2.6×10−14, n = 93,440), increased waist-to-hip ratio (p = 1.8×10−5, n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10−3, n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL- cholesterol concentrations (p = 4.5×10−13, n = 96,748) and decreased BMI (p = 1.4×10−4, n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance