Sixteen new lung function signals identified through 1000 Genomes Project reference panel imputation

Lung function measures are used in the diagnosis of chronic obstructive pulmonary disease. In 38,199 European ancestry individuals, we studied genome-wide association of forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and FEV1/FVC with 1000 Genomes Project (Phase 1) imputed genotypes and followed up top associations in 54,550 Europeans. We identify 14 novel loci (P<5x10-8) in or near ENSA, RNU5F-1, KCNS3, AK097794, ASTN2, LHX3, CCDC91, TBX3, TRIP11, RIN3, TEKT5, LTBP4, MN1, AP1S2, and two novel signals at known loci NPNT and GPR126, providing a basis for new understanding of the genetic determinants of these traits and pulmonary diseases in which they are altered

Novel loci for glycaemic and obesity-related traits achieving genome-wide significance (<i>p</i><5x10^-8).

<p>Novel loci for glycaemic and obesity-related traits achieving genome-wide significance (<i>p</i><5x10^-8).</p

Loci with multiple distinct signals of association with glycaemic and obesity-related traits achieving “locus-wide” significance in conditional analysis (<i>p</i>_COND<10⁻⁵).

<p>Loci with multiple distinct signals of association with glycaemic and obesity-related traits achieving “locus-wide” significance in conditional analysis (<i>p</i>_COND<10⁻⁵).</p

Association signals for glycaemic and obesity-related traits for which the 99% credible sets contain no more than 20 variants.

<p>Association signals for glycaemic and obesity-related traits for which the 99% credible sets contain no more than 20 variants.</p

Broad category functional annotation (A) and cell-type specific annotation (B) of credible set variants.

<p>On the x-axis is each category of broad functional annotation (A) or cell-type specific annotation (B). The fraction of credible set variants that overlap with each category is shown on y-axis. The overlapping variants are further broken down into either variants that exist in both the 1000 Genomes and HapMap reference panel (green) or those that exist only in the 1000 Genomes reference panel (red). TFBS, transcription factor binding site; ncRNA, non-coding RNA; UTR, untranslated regions; GM12878, lymphoblastoid cell line from European ancestry female; hESC, H1 human embryonic stem cells; hASC(t1), human pre-adipocytes; hASC(t4), mature human adipocytes; HepG2, liver carcinoma cell-line; HMEC, human mammary epithelial cells; HSMM, human skeletal muscle myoblasts; HUVEC, human umbilical vein endothelial cells; K562, human myelogenous leukemia cell-line; NHEK, normal human epidermal keratinocytes; NHLF, normal human lung fibroblasts.</p

Regional plots of multiple distinct signals at WHR_adjBMI locus <i>RSPO3</i> (A), FG loci <i>G6PC2</i> (B) and <i>GCK</i> (C).

<p>Regional plots for each locus are displayed from: the unconditional meta-analysis (left); the exact conditional meta-analysis for the primary signal after adjustment for the index variant for the secondary signal (middle); and the exact conditional meta-analysis for the secondary signal after adjustment for the index variant for the primary signal (right). The sample sizes vary due to the availability of the well imputed index SNPs of the primary and secondary signals. Directly genotyped or imputed SNPs are plotted with their association <i>P</i> values (on a -log₁₀ scale) as a function of genomic position (NCBI Build 37). Estimated recombination rates are plotted to reflect the local LD structure around the associated SNPs and their correlated proxies (according to a blue to red scale from <i>r</i>^<i>2</i> = 0 to 1, based on pairwise EUR <i>r</i>^<i>2</i> values from the 1000 Genomes June 2011 release). SNP annotations are as follows: circles, no annotation; downward triangles, nonsynonymous; squares, coding or 3′ UTR; asterisks, TFBScons (in a conserved region predicted to be a transcription factor binding site); squares with an X, MCS44 placental (in a region highly conserved in placental mammals).</p

Meta-analysis results of Mendelian randomization analyses on effect of <i>FTO</i>-derived adiposity on cardiovascular and metabolic disease: quantitative phenotypes.

a<p>Beta coefficient corresponds to one-unit increase in BMI (kg/m²).</p>b<p>Beta coefficient corresponds to per-allele change.</p>c<p>Values were transformed to natural logarithm scale prior to analysis.</p

Association between <i>FTO</i> and incident heart failure in 2,863 cases and 44,400 controls.

<p>Estimates (ES) are shown on a hazard ratio scale per number of effect alleles. The assigned weight for each study in the meta-analysis is shown in percent (% Weight). For cohort abbreviations and references, see <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001474#pmed.1001474.s003" target="_blank">Table S1</a>.</p

Comparison of our study with previous Mendelian randomization studies of adiposity on cardiometabolic phenotypes.

a<p>No formal MR study, although the association of <i>FTO</i> and T2D is well known.</p><p>N.A, not applicable.</p

Meta-analysis results of Mendelian randomization analyses on effect of <i>FTO</i>-derived adiposity on cardiovascular and metabolic disease: dichotomous outcomes.

a<p>OR/HR corresponds to one-unit increase in BMI (kg/m²).</p>b<p>OR/HR corresponds to per-allele change.</p>c<p>Only one study; meta-analysis not performed.</p><p>HR, hazard ratio.</p