We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 cases and 64,762 controls of European descent, followed by genotyping of top association signals in 60,738 additional individuals. This genomic analysis identified 13 novel loci harboring one or more SNPs that were associated with CAD at P<5×10−8 and confirmed the association of 10 of 12 previously reported CAD loci. The 13 novel loci displayed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6 to 17 percent increase in the risk of CAD per allele. Notably, only three of the novel loci displayed significant association with traditional CAD risk factors, while the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the novel CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits.

We conducted genome-wide association analyses of mean leukocyte telomere length in 2,917 subjects and follow-up replication analyses in 9,492 and identified a locus on 3q26 encompassing the telomerase RNA component TERC, with compelling evidence for association (rs12696304, combined P value 3.72×10 −14 ). Each copy of the minor allele of rs12696304 was associated with ≈75 base pairs shorter mean telomere length equivalent to ≈3.6 years of age-related attrition of mean telomere length.Telomeres are structures at the ends of eukaryotic chromosomes that are made up of a simple repetitive sequence (in humans TTAGGG) and involved in maintaining genomic stability and regulating cellular proliferation. 1 Telomere length (TL) plays an important role in determining telomere function. In somatic cells TL progressively shortens with each mitotic division due to the inability of DNA polymerase to fully replicate the 3 end of the DNA strand. Cellular senescence and subsequent death often occurs when the mean TL Correspondence to: Nilesh J Samani, Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Groby Road, Leicester, LE3 9QP, UK, Telephone: +441162563021; Facsimile: +441162875792; njs@le.ac.uk. AUTHOR CONTRIBUTIONS N.J.S and T.S. conceived the study. V.C., M.M., and P.vd.H. designed the laboratory work and conducted the analyses. V.C., P.S.B., M.K., J.M., I.M-L., and R.A.d.B. undertook the laboratory work. A.J.B provided bioinformatics support and S.R., C.N., and N.S. undertook statistical support. A.S.H and N.J.S recruited and provided samples and data from the BHF Family Heart Study, W.T.C.C.C. and W.O. from the UKBS samples, A.H.G., P.R.B., M.D.T., and N.J.S from the GRAPHIC study, G.Z., A.M.V., H.B., and T.S. from the TwinsUK study and D.J.vV., W.H.vG., and G.N. from the PREVEND Study. J.R.T. oversaw the statistical analysis. The paper was written by V.C., M.M. and N.J.S. All authors contributed to the final version of the manuscript. *These authors contributed equally to this work. #These authors contributed equally to this work. Figure 1B) in both cohorts. CONFLICTS OF INTEREST STATEMENTWe analysed the association of T/S ratio adjusted for age and gender with genotype individually in the BHF-FHS (Supplementary Table 2A) and UKBS (Supplementary Tables 2B) cohorts and also in a combined analysis of the two cohorts. The quantile-quantile plots for each cohort are shown in Supplementary Figure 1C and the power to detect associations in Supplementary Figure 1D. The genomic inflation control factors for the BHF-FHS and UKBS analyses were 1.02 and 0.99, respectively. We screened the results from the combined analysis for SNPs that showed concordance in their results in the individual analyses (i.e. at least nominally significant (P<0.05) in both cohorts with beta coefficients in the same direction). These criteria identified 180 SNPs at p<1×10 −3 and 24 SNPs at p<1×10 −4 . SNPs achieving a combined P<5×10 −5 are shown in Supplementary Table 2C. Notably, neither the previously repor...

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10(-5)) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10(-5)). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10(-10), odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression.

During 2014 and 2015, NASA's Neutron star Interior Composition Explorer (NICER) mission proceeded successfully through Phase C, Design and Development. An X-ray (0.2-12 keV) astrophysics payload destined for the International Space Station, NICER is manifested for launch in early 2017 on the Commercial Resupply Services SpaceX-11 flight. Its scientific objectives are to investigate the internal structure, dynamics, and energetics of neutron stars, the densest objects in the universe. During Phase C, flight components including optics, detectors, the optical bench, pointing actuators, electronics, and others were subjected to environmental testing and integrated to form the flight payload. A custom-built facility was used to co-align and integrate the X-ray "concentrator" optics and silicon-drift detectors. Ground calibration provided robust performance measures of the optical (at NASA's Goddard Space Flight Center) and detector (at the Massachusetts Institute of Technology) subsystems, while comprehensive functional tests prior to payload-level environmental testing met all instrument performance requirements. We describe here the implementation of NICER's major subsystems, summarize their performance and calibration, and outline the component-level testing that was successfully applied.