A Genome-Wide Association Study of the Metabolic Syndrome in Indian Asian Men

We conducted a two-stage genome-wide association study to identify common genetic variation altering risk of the metabolic syndrome and related phenotypes in Indian Asian men, who have a high prevalence of these conditions. In Stage 1, approximately 317,000 single nucleotide polymorphisms were genotyped in 2700 individuals, from which 1500 SNPs were selected to be genotyped in a further 2300 individuals. Selection for inclusion in Stage 1 was based on four metabolic syndrome component traits: HDL-cholesterol, plasma glucose and Type 2 diabetes, abdominal obesity measured by waist to hip ratio, and diastolic blood pressure. Association was tested with these four traits and a composite metabolic syndrome phenotype. Four SNPs reaching significance level p0.8 were found in genes CETP and LPL, associated with HDL-cholesterol. These associations have already been reported in Indian Asians and in Europeans. Five additional loci harboured SNPs significant at p0.5 for HDL-cholesterol, type 2 diabetes or diastolic blood pressure. Our results suggest that the primary genetic determinants of metabolic syndrome are the same in Indian Asians as in other populations, despite the higher prevalence. Further, we found little evidence of a common genetic basis for metabolic syndrome traits in our sample of Indian Asian men

A Genome-Wide Association Study of the Metabolic Syndrome in Indian Asian Men

We conducted a two-stage genome-wide association study to identify common genetic variation altering risk of the metabolic syndrome and related phenotypes in Indian Asian men, who have a high prevalence of these conditions. In Stage 1, approximately 317,000 single nucleotide polymorphisms were genotyped in 2700 individuals, from which 1500 SNPs were selected to be genotyped in a further 2300 individuals. Selection for inclusion in Stage 1 was based on four metabolic syndrome component traits: HDL-cholesterol, plasma glucose and Type 2 diabetes, abdominal obesity measured by waist to hip ratio, and diastolic blood pressure. Association was tested with these four traits and a composite metabolic syndrome phenotype. Four SNPs reaching significance level p<5×10−7 and with posterior probability of association >0.8 were found in genes CETP and LPL, associated with HDL-cholesterol. These associations have already been reported in Indian Asians and in Europeans. Five additional loci harboured SNPs significant at p<10−6 and posterior probability >0.5 for HDL-cholesterol, type 2 diabetes or diastolic blood pressure. Our results suggest that the primary genetic determinants of metabolic syndrome are the same in Indian Asians as in other populations, despite the higher prevalence. Further, we found little evidence of a common genetic basis for metabolic syndrome traits in our sample of Indian Asian men

HAPRAP: a haplotype-based iterative method for statistical fine mapping using GWAS summary statistics

Motivation Fine mapping is a widely used approach for identifying the causal variant(s) at disease-associated loci. Standard methods (e.g. multiple regression) require individual level genotypes. Recent fine mapping methods using summary-level data require the pairwise correlation coefficients (r2 ) of the variants. However, haplotypes rather than pairwise r2 , are the true biological representation of linkage disequilibrium (LD) among multiple loci. In this article, we present an empirical iterative method, HAPlotype Regional Association analysis Program (HAPRAP), that enables fine mapping using summary statistics and haplotype information from an individual-level reference panel. Results Simulations with individual-level genotypes show that the results of HAPRAP and multiple regression are highly consistent. In simulation with summary-level data, we demonstrate that HAPRAP is less sensitive to poor LD estimates. In a parametric simulation using Genetic Investigation of ANthropometric Traits height data, HAPRAP performs well with a small training sample size (N < 2000) while other methods become suboptimal. Moreover, HAPRAP’s performance is not affected substantially by single nucleotide polymorphisms (SNPs) with low minor allele frequencies. We applied the method to existing quantitative trait and binary outcome meta-analyses (human height, QTc interval and gallbladder disease); all previous reported association signals were replicated and two additional variants were independently associated with human height. Due to the growing availability of summary level data, the value of HAPRAP is likely to increase markedly for future analyses (e.g. functional prediction and identification of instruments for Mendelian randomization)

Quantum circuits with many photons on a programmable nanophotonic chip

Growing interest in quantum computing for practical applications has led to a surge in the availability of programmable machines for executing quantum algorithms. Present day photonic quantum computers have been limited either to non-deterministic operation, low photon numbers and rates, or fixed random gate sequences. Here we introduce a full-stack hardware-software system for executing many-photon quantum circuits using integrated nanophotonics: a programmable chip, operating at room temperature and interfaced with a fully automated control system. It enables remote users to execute quantum algorithms requiring up to eight modes of strongly squeezed vacuum initialized as two-mode squeezed states in single temporal modes, a fully general and programmable four-mode interferometer, and genuine photon number-resolving readout on all outputs. Multi-photon detection events with photon numbers and rates exceeding any previous quantum optical demonstration on a programmable device are made possible by strong squeezing and high sampling rates. We verify the non-classicality of the device output, and use the platform to carry out proof-of-principle demonstrations of three quantum algorithms: Gaussian boson sampling, molecular vibronic spectra, and graph similarity

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD

Sixty-five common genetic variants and prediction of type 2 diabetes.

We developed a 65 type 2 diabetes (T2D) variant-weighted gene score to examine the impact on T2D risk assessment in a U.K.-based consortium of prospective studies, with subjects initially free from T2D (N = 13,294; 37.3% women; mean age 58.5 [38-99] years). We compared the performance of the gene score with the phenotypically derived Framingham Offspring Study T2D risk model and then the two in combination. Over the median 10 years of follow-up, 804 participants developed T2D. The odds ratio for T2D (top vs. bottom quintiles of gene score) was 2.70 (95% CI 2.12-3.43). With a 10% false-positive rate, the genetic score alone detected 19.9% incident cases, the Framingham risk model 30.7%, and together 37.3%. The respective area under the receiver operator characteristic curves were 0.60 (95% CI 0.58-0.62), 0.75 (95% CI 0.73 to 0.77), and 0.76 (95% CI 0.75 to 0.78). The combined risk score net reclassification improvement (NRI) was 8.1% (5.0 to 11.2; P = 3.31 × 10(-7)). While BMI stratification into tertiles influenced the NRI (BMI ≤24.5 kg/m(2), 27.6% [95% CI 17.7-37.5], P = 4.82 × 10(-8); 24.5-27.5 kg/m(2), 11.6% [95% CI 5.8-17.4], P = 9.88 × 10(-5); >27.5 kg/m(2), 2.6% [95% CI -1.4 to 6.6], P = 0.20), age categories did not. The addition of the gene score to a phenotypic risk model leads to a potentially clinically important improvement in discrimination of incident T2D

Replication and Characterization of Association between ABO SNPs and Red Blood Cell Traits by Meta-Analysis in Europeans.

Red blood cell (RBC) traits are routinely measured in clinical practice as important markers of health. Deviations from the physiological ranges are usually a sign of disease, although variation between healthy individuals also occurs, at least partly due to genetic factors. Recent large scale genetic studies identified loci associated with one or more of these traits; further characterization of known loci and identification of new loci is necessary to better understand their role in health and disease and to identify potential molecular mechanisms. We performed meta-analysis of Metabochip association results for six RBC traits-hemoglobin concentration (Hb), hematocrit (Hct), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV) and red blood cell count (RCC)-in 11 093 Europeans from seven studies of the UCL-LSHTM-Edinburgh-Bristol (UCLEB) Consortium. We identified 394 non-overlapping SNPs in five loci at genome-wide significance: 6p22.1-6p21.33 (with HFE among others), 6q23.2 (with HBS1L among others), 6q23.3 (contains no genes), 9q34.3 (only ABO gene) and 22q13.1 (with TMPRSS6 among others), replicating previous findings of association with RBC traits at these loci and extending them by imputation to 1000 Genomes. We further characterized associations between ABO SNPs and three traits: hemoglobin, hematocrit and red blood cell count, replicating them in an independent cohort. Conditional analyses indicated the independent association of each of these traits with ABO SNPs and a role for blood group O in mediating the association. The 15 most significant RBC-associated ABO SNPs were also associated with five cardiometabolic traits, with discordance in the direction of effect between groups of traits, suggesting that ABO may act through more than one mechanism to influence cardiometabolic risk.British Heart Foundation (Grant ID: RG/10/12/28456, RG/08/013/25942, RG/13/16/30528, RG/98002, RG/07/008/23674); Medical Research Council (Grant ID: G0000934, G0500877, MC_UU_12019/1, K013351); Wellcome Trust (Grant ID: 068545/Z/02, 097451/Z/11/Z); European Commission Framework Programme 6 (Grant ID: 018996); French Ministry of Research; Department of Health Policy Research Programme (England); Chief Scientist Office of Scotland (Grant ID: CZB/4/672, CZQ/1/38); National Institute on Ageing (NIA) (Grant ID: AG1764406S1, 5RO1AG13196); Pfizer plc (Unrestricted Investigator Led Grant); Diabetes UK (Clinical Research Fellowship 10/0003985); Stroke Association; National Heart Lung and Blood Institute (5RO1HL036310); Agency for Health Care Policy Research (HS06516); John D. and Catherine T. MacArthur Foundation Research Networks on Successful Midlife Development and Socio-economic Status and Health; Swiss National Science Foundation (33CSCO-122661); GlaxoSmithKline. Faculty of Biology and Medicine of Lausanne,Switzerland.This is the final version of the article. It first appeared from Public Library of Science (PLOS) via http://dx.doi.org/10.1371/journal.pone.015691

A Replication Study of GWAS-Derived Lipid Genes in Asian Indians: The Chromosomal Region 11q23.3 Harbors Loci Contributing to Triglycerides

Recent genome-wide association scans (GWAS) and meta-analysis studies on European populations have identified many genes previously implicated in lipid regulation. Validation of these loci on different global populations is important in determining their clinical relevance, particularly for development of novel drug targets for treating and preventing diabetic dyslipidemia and coronary artery disease (CAD). In an attempt to replicate GWAS findings on a non-European sample, we examined the role of six of these loci (CELSR2-PSRC1-SORT1 rs599839; CDKN2A-2B rs1333049; BUD13-ZNF259 rs964184; ZNF259 rs12286037; CETP rs3764261; APOE-C1-C4-C2 rs4420638) in our Asian Indian cohort from the Sikh Diabetes Study (SDS) comprising 3,781 individuals (2,902 from Punjab and 879 from the US). Two of the six SNPs examined showed convincing replication in these populations of Asian Indian origin. Our study confirmed a strong association of CETP rs3764261 with high-density lipoprotein cholesterol (HDL-C) (p = 2.03×10−26). Our results also showed significant associations of two GWAS SNPs (rs964184 and rs12286037) from BUD13-ZNF259 near the APOA5-A4-C3-A1 genes with triglyceride (TG) levels in this Asian Indian cohort (rs964184: p = 1.74×10−17; rs12286037: p = 1.58×10−2). We further explored 45 SNPs in a ∼195 kb region within the chromosomal region 11q23.3 (encompassing the BUD13-ZNF259, APOA5-A4-C3-A1, and SIK3 genes) in 8,530 Asian Indians from the London Life Sciences Population (LOLIPOP) (UK) and SDS cohorts. Five more SNPs revealed significant associations with TG in both cohorts individually as well as in a joint meta-analysis. However, the strongest signal for TG remained with BUD13-ZNF259 (rs964184: p = 1.06×10−39). Future targeted deep sequencing and functional studies should enhance our understanding of the clinical relevance of these genes in dyslipidemia and hypertriglyceridemia (HTG) and, consequently, diabetes and CAD

Plasma urate concentration and risk of coronary heart disease: a Mendelian randomisation analysis.

BACKGROUND: Increased circulating plasma urate concentration is associated with an increased risk of coronary heart disease, but the extent of any causative effect of urate on risk of coronary heart disease is still unclear. In this study, we aimed to clarify any causal role of urate on coronary heart disease risk using Mendelian randomisation analysis. METHODS: We first did a fixed-effects meta-analysis of the observational association of plasma urate and risk of coronary heart disease. We then used a conventional Mendelian randomisation approach to investigate the causal relevance using a genetic instrument based on 31 urate-associated single nucleotide polymorphisms (SNPs). To account for potential pleiotropic associations of certain SNPs with risk factors other than urate, we additionally did both a multivariable Mendelian randomisation analysis, in which the genetic associations of SNPs with systolic and diastolic blood pressure, HDL cholesterol, and triglycerides were included as covariates, and an Egger Mendelian randomisation (MR-Egger) analysis to estimate a causal effect accounting for unmeasured pleiotropy. FINDINGS: In the meta-analysis of 17 prospective observational studies (166 486 individuals; 9784 coronary heart disease events) a 1 SD higher urate concentration was associated with an odds ratio (OR) for coronary heart disease of 1·07 (95% CI 1·04-1·10). The corresponding OR estimates from the conventional, multivariable adjusted, and Egger Mendelian randomisation analysis (58 studies; 198 598 individuals; 65 877 events) were 1·18 (95% CI 1·08-1·29), 1·10 (1·00-1·22), and 1·05 (0·92-1·20), respectively, per 1 SD increment in plasma urate. INTERPRETATION: Conventional and multivariate Mendelian randomisation analysis implicates a causal role for urate in the development of coronary heart disease, but these estimates might be inflated by hidden pleiotropy. Egger Mendelian randomisation analysis, which accounts for pleiotropy but has less statistical power, suggests there might be no causal effect. These results might help investigators to determine the priority of trials of urate lowering for the prevention of coronary heart disease compared with other potential interventions. FUNDING: UK National Institute for Health Research, British Heart Foundation, and UK Medical Research Council

Population genomics of cardiometabolic traits: design of the University College London-London School of Hygiene and Tropical Medicine-Edinburgh-Bristol (UCLEB) Consortium

Substantial advances have been made in identifying common genetic variants influencing cardiometabolic traits and disease outcomes through genome wide association studies. Nevertheless, gaps in knowledge remain and new questions have arisen regarding the population relevance, mechanisms, and applications for healthcare. Using a new high-resolution custom single nucleotide polymorphism (SNP) array (Metabochip) incorporating dense coverage of genomic regions linked to cardiometabolic disease, the University College-London School-Edinburgh-Bristol (UCLEB) consortium of highly-phenotyped population-based prospective studies, aims to: (1) fine map functionally relevant SNPs; (2) precisely estimate individual absolute and population attributable risks based on individual SNPs and their combination; (3) investigate mechanisms leading to altered risk factor profiles and CVD events; and (4) use Mendelian randomisation to undertake studies of the causal role in CVD of a range of cardiovascular biomarkers to inform public health policy and help develop new preventative therapies.Tina Shah ... Debbie A. Lawlor ... et al. on behalf of the UCLEB Consortiu