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Sökning: WFRF:(Andres Christian) > (2015-2019)

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1.
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2.
  • Abolfathi, Bela, et al. (författare)
  • The Fourteenth Data Release of the Sloan Digital Sky Survey : First Spectroscopic Data from the Extended Baryon Oscillation Spectroscopic Survey and from the Second Phase of the Apache Point Observatory Galactic Evolution Experiment
  • 2018
  • Ingår i: Astrophysical Journal Supplement Series. - : IOP Publishing Ltd. - 0067-0049 .- 1538-4365. ; 235:2
  • Tidskriftsartikel (refereegranskat)abstract
    • The fourth generation of the Sloan Digital Sky Survey (SDSS-IV) has been in operation since 2014 July. This paper describes the second data release from this phase, and the 14th from SDSS overall (making this Data Release Fourteen or DR14). This release makes the data taken by SDSS-IV in its first two years of operation (2014-2016 July) public. Like all previous SDSS releases, DR14 is cumulative, including the most recent reductions and calibrations of all data taken by SDSS since the first phase began operations in 2000. New in DR14 is the first public release of data from the extended Baryon Oscillation Spectroscopic Survey; the first data from the second phase of the Apache Point Observatory (APO) Galactic Evolution Experiment (APOGEE-2), including stellar parameter estimates from an innovative data-driven machine-learning algorithm known as "The Cannon"; and almost twice as many data cubes from the Mapping Nearby Galaxies at APO (MaNGA) survey as were in the previous release (N = 2812 in total). This paper describes the location and format of the publicly available data from the SDSS-IV surveys. We provide references to the important technical papers describing how these data have been taken (both targeting and observation details) and processed for scientific use. The SDSS web site (www.sdss.org) has been updated for this release and provides links to data downloads, as well as tutorials and examples of data use. SDSS-IV is planning to continue to collect astronomical data until 2020 and will be followed by SDSS-V.
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3.
  • Gaulton, Kyle J, et al. (författare)
  • Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.
  • 2015
  • Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 47:12, s. 1415-1415
  • Tidskriftsartikel (refereegranskat)abstract
    • We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.
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4.
  • Pattaro, Cristian, et al. (författare)
  • Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function
  • 2016
  • Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
  • Tidskriftsartikel (refereegranskat)abstract
    • Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.
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5.
  • Scott, Robert A., et al. (författare)
  • An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans
  • 2017
  • Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 66:11, s. 2888-2902
  • Tidskriftsartikel (refereegranskat)abstract
    • To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 x 10(-8)), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.
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6.
  • Flannick, Jason, et al. (författare)
  • Data Descriptor : Sequence data and association statistics from 12,940 type 2 diabetes cases and controls
  • 2017
  • Ingår i: Scientific Data. - : Springer Science and Business Media LLC. - 2052-4463. ; 4
  • Tidskriftsartikel (refereegranskat)abstract
    • To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1-5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (> 80% of low-frequency coding variants in similar to ~82 K Europeans via the exome chip, and similar to ~90% of low-frequency non-coding variants in similar to ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D.
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7.
  • Fuchsberger, Christian, et al. (författare)
  • The genetic architecture of type 2 diabetes
  • 2016
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 536:7614, s. 41-47
  • Tidskriftsartikel (refereegranskat)abstract
    • The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.
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8.
  • Horikoshi, Momoko, et al. (författare)
  • Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation.
  • 2015
  • Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 11:7
  • Tidskriftsartikel (refereegranskat)abstract
    • Reference panels from the 1000 Genomes (1000G) Project Consortium provide near complete coverage of common and low-frequency genetic variation with minor allele frequency ≥0.5% across European ancestry populations. Within the European Network for Genetic and Genomic Epidemiology (ENGAGE) Consortium, we have undertaken the first large-scale meta-analysis of genome-wide association studies (GWAS), supplemented by 1000G imputation, for four quantitative glycaemic and obesity-related traits, in up to 87,048 individuals of European ancestry. We identified two loci for body mass index (BMI) at genome-wide significance, and two for fasting glucose (FG), none of which has been previously reported in larger meta-analysis efforts to combine GWAS of European ancestry. Through conditional analysis, we also detected multiple distinct signals of association mapping to established loci for waist-hip ratio adjusted for BMI (RSPO3) and FG (GCK and G6PC2). The index variant for one association signal at the G6PC2 locus is a low-frequency coding allele, H177Y, which has recently been demonstrated to have a functional role in glucose regulation. Fine-mapping analyses revealed that the non-coding variants most likely to drive association signals at established and novel loci were enriched for overlap with enhancer elements, which for FG mapped to promoter and transcription factor binding sites in pancreatic islets, in particular. Our study demonstrates that 1000G imputation and genetic fine-mapping of common and low-frequency variant association signals at GWAS loci, integrated with genomic annotation in relevant tissues, can provide insight into the functional and regulatory mechanisms through which their effects on glycaemic and obesity-related traits are mediated.
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9.
  • Locke, Adam E, et al. (författare)
  • Genetic studies of body mass index yield new insights for obesity biology.
  • 2015
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
  • Tidskriftsartikel (refereegranskat)abstract
    • Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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10.
  • Shungin, Dmitry, et al. (författare)
  • New genetic loci link adipose and insulin biology to body fat distribution.
  • 2015
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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11.
  • van Rheenen, Wouter, et al. (författare)
  • Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis
  • 2016
  • Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 48:9, s. 1043-1048
  • Tidskriftsartikel (refereegranskat)abstract
    • To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.
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12.
  • Wuttke, Matthias, et al. (författare)
  • A catalog of genetic loci associated with kidney function from analyses of a million individuals
  • 2019
  • Ingår i: Nature Genetics. - : NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 51:6, s. 957-972
  • Tidskriftsartikel (refereegranskat)abstract
    • Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
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13.
  • Ademuyiwa, Adesoji O., et al. (författare)
  • Determinants of morbidity and mortality following emergency abdominal surgery in children in low-income and middle-income countries
  • 2016
  • Ingår i: BMJ Global Health. - : BMJ Publishing Group Ltd. - 2059-7908. ; 1:4
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Child health is a key priority on the global health agenda, yet the provision of essential and emergency surgery in children is patchy in resource-poor regions. This study was aimed to determine the mortality risk for emergency abdominal paediatric surgery in low-income countries globally.Methods: Multicentre, international, prospective, cohort study. Self-selected surgical units performing emergency abdominal surgery submitted prespecified data for consecutive children aged <16 years during a 2-week period between July and December 2014. The United Nation's Human Development Index (HDI) was used to stratify countries. The main outcome measure was 30-day postoperative mortality, analysed by multilevel logistic regression.Results: This study included 1409 patients from 253 centres in 43 countries; 282 children were under 2 years of age. Among them, 265 (18.8%) were from low-HDI, 450 (31.9%) from middle-HDI and 694 (49.3%) from high-HDI countries. The most common operations performed were appendectomy, small bowel resection, pyloromyotomy and correction of intussusception. After adjustment for patient and hospital risk factors, child mortality at 30 days was significantly higher in low-HDI (adjusted OR 7.14 (95% CI 2.52 to 20.23), p<0.001) and middle-HDI (4.42 (1.44 to 13.56), p=0.009) countries compared with high-HDI countries, translating to 40 excess deaths per 1000 procedures performed.Conclusions: Adjusted mortality in children following emergency abdominal surgery may be as high as 7 times greater in low-HDI and middle-HDI countries compared with high-HDI countries. Effective provision of emergency essential surgery should be a key priority for global child health agendas.
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14.
  • Aguado, D. S., et al. (författare)
  • The Fifteenth Data Release of the Sloan Digital Sky Surveys : First Release of MaNGA-derived Quantities, Data Visualization Tools, and Stellar Library
  • 2019
  • Ingår i: Astrophysical Journal Supplement Series. - : Institute of Physics Publishing (IOPP). - 0067-0049 .- 1538-4365. ; 240:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Twenty years have passed since first light for the Sloan Digital Sky Survey (SDSS). Here, we release data taken by the fourth phase of SDSS (SDSS-IV) across its first three years of operation (2014 July-2017 July). This is the third data release for SDSS-IV, and the 15th from SDSS (Data Release Fifteen; DR15). New data come from MaNGA-we release 4824 data cubes, as well as the first stellar spectra in the MaNGA Stellar Library (MaStar), the first set of survey-supported analysis products (e.g., stellar and gas kinematics, emission-line and other maps) from the MaNGA Data Analysis Pipeline, and a new data visualization and access tool we call "Marvin." The next data release, DR16, will include new data from both APOGEE-2 and eBOSS; those surveys release no new data here, but we document updates and corrections to their data processing pipelines. The release is cumulative; it also includes the most recent reductions and calibrations of all data taken by SDSS since first light. In this paper, we describe the location and format of the data and tools and cite technical references describing how it was obtained and processed. The SDSS website (www.sdss.org) has also been updated, providing links to data downloads, tutorials, and examples of data use. Although SDSS-IV will continue to collect astronomical data until 2020, and will be followed by SDSS-V (2020-2025), we end this paper by describing plans to ensure the sustainability of the SDSS data archive for many years beyond the collection of data.
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15.
  • Blanton, Michael R., et al. (författare)
  • Sloan Digital Sky Survey IV : Mapping the Milky Way, Nearby Galaxies, and the Distant Universe
  • 2017
  • Ingår i: Astronomical Journal. - : IOP Publishing Ltd. - 0004-6256 .- 1538-3881. ; 154:1
  • Tidskriftsartikel (refereegranskat)abstract
    • We describe the Sloan Digital Sky Survey IV (SDSS-IV), a project encompassing three major spectroscopic programs. The Apache Point Observatory Galactic Evolution Experiment 2 (APOGEE-2) is observing hundreds of thousands of Milky Way stars at high resolution and. high signal-to-noise ratios in the near-infrared. The Mapping Nearby Galaxies at Apache Point Observatory (MaNGA) survey is obtaining spatially resolved spectroscopy for thousands of nearby galaxies (median z similar to 0.03). The extended Baryon Oscillation Spectroscopic Survey (eBOSS) is mapping the galaxy, quasar, and neutral gas distributions between z similar to 0.6 and 3.5 to constrain cosmology using baryon acoustic oscillations, redshift space distortions, and the shape of the power spectrum. Within eBOSS, we are conducting two major subprograms: the SPectroscopic IDentification of eROSITA Sources (SPIDERS), investigating X-ray AGNs. and galaxies in X-ray clusters, and the Time Domain Spectroscopic Survey (TDSS), obtaining spectra of variable sources. All programs use the 2.5 m Sloan Foundation Telescope at the. Apache Point Observatory; observations there began in Summer 2014. APOGEE-2 also operates a second near-infrared spectrograph at the 2.5 m du Pont Telescope at Las Campanas Observatory, with observations beginning in early 2017. Observations at both facilities are scheduled to continue through 2020. In keeping with previous SDSS policy, SDSS-IV provides regularly scheduled public data releases; the first one, Data Release 13, was made available in 2016 July.
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16.
  • Fall, Tove, et al. (författare)
  • Age- and sex-specific causal effects of adiposity on cardiovascular risk factors
  • 2015
  • Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 64:5, s. 1841-1852
  • Tidskriftsartikel (refereegranskat)abstract
    • Observational studies have reported different effects of adiposity on cardiovascular risk factors across age and sex. Since cardiovascular risk factors are enriched in obese individuals, it has not been easy to dissect the effects of adiposity from those of other risk factors. We used a Mendelian randomization approach, applying a set of 32 genetic markers to estimate the causal effect of adiposity on blood pressure, glycemic indices, circulating lipid levels, and markers of inflammation and liver disease in up to 67,553 individuals. All analyses were stratified by age (cutoff 55 years of age) and sex. The genetic score was associated with BMI in both nonstratified analysis (P = 2.8 × 10(-107)) and stratified analyses (all P < 3.3 × 10(-30)). We found evidence of a causal effect of adiposity on blood pressure, fasting levels of insulin, C-reactive protein, interleukin-6, HDL cholesterol, and triglycerides in a nonstratified analysis and in the <55-year stratum. Further, we found evidence of a smaller causal effect on total cholesterol (P for difference = 0.015) in the ≥55-year stratum than in the <55-year stratum, a finding that could be explained by biology, survival bias, or differential medication. In conclusion, this study extends previous knowledge of the effects of adiposity by providing sex- and age-specific causal estimates on cardiovascular risk factors.
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17.
  • Gorski, Mathias, et al. (författare)
  • 1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function.
  • 2017
  • Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7
  • Tidskriftsartikel (refereegranskat)abstract
    • HapMap imputed genome-wide association studies (GWAS) have revealed >50 loci at which common variants with minor allele frequency >5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-analysis of kidney function based on the estimated glomerular filtration rate (eGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value < 5 × 10(-8) previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR < 0.05) genes and 127 significantly (FDR < 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until whole-genome sequencing becomes feasible in large samples.
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18.
  • Huffman, Jennifer E., et al. (författare)
  • Modulation of Genetic Associations with Serum Urate Levels by Body-Mass-Index in Humans
  • 2015
  • Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:3
  • Tidskriftsartikel (refereegranskat)abstract
    • We tested for interactions between body mass index (BMI) and common genetic variants affecting serum urate levels, genome-wide, in up to 42569 participants. Both stratified genome-wide association (GWAS) analyses, in lean, overweight and obese individuals, and regression-type analyses in a non BMI-stratified overall sample were performed. The former did not uncover any novel locus with a major main effect, but supported modulation of effects for some known and potentially new urate loci. The latter highlighted a SNP at RBFOX3 reaching genome-wide significant level (effect size 0.014, 95% CI 0.008-0.02, P-inter= 2.6 x 10(-8)). Two top loci in interaction term analyses, RBFOX3 and ERO1LB-EDAR-ADD, also displayed suggestive differences in main effect size between the lean and obese strata. All top ranking loci for urate effect differences between BMI categories were novel and most had small magnitude but opposite direction effects between strata. They include the locus RBMS1-TANK (men, Pdifflean-overweight= 4.7 x 10(-8)), a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight= 9.1 x 10(-8)), regulating adipocytes-produced estradiol. The top-ranking known urate loci was ABCG2, the strongest known gout risk locus, with an effect halved in obese compared to lean men (Pdifflean-obese= 2 x 10(-4)). Finally, pathway analysis suggested a role for N-glycan biosynthesis as a prominent urate-associated pathway in the lean stratum. These results illustrate a potentially powerful way to monitor changes occurring in obesogenic environment.
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19.
  • Mahajan, Anubha, et al. (författare)
  • Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps
  • 2018
  • Ingår i: Nature Genetics. - : NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 50:11, s. 1505-
  • Tidskriftsartikel (refereegranskat)abstract
    • We expanded GWAS discovery for type 2 diabetes (T2D) by combining data from 898,130 European-descent individuals (9% cases), after imputation to high-density reference panels. With these data, we (i) extend the inventory of T2D-risk variants (243 loci,135 newly implicated in T2D predisposition, comprising 403 distinct association signals); (ii) enrich discovery of lower-frequency risk alleles (80 index variants with minor allele frequency <5%,14 with estimated allelic odds ratio >2); (iii) substantially improve fine-mapping of causal variants (at 51 signals, one variant accounted for >80% posterior probability of association (PPA)); (iv) extend fine-mapping through integration of tissue-specific epigenomic information (islet regulatory annotations extend the number of variants with PPA >80% to 73); (v) highlight validated therapeutic targets (18 genes with associations attributable to coding variants); and (vi) demonstrate enhanced potential for clinical translation (genome-wide chip heritability explains 18% of T2D risk; individuals in the extremes of a T2D polygenic risk score differ more than ninefold in prevalence).
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20.
  • Manning, Alisa, et al. (författare)
  • A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk
  • 2017
  • Ingår i: Diabetes. - : AMER DIABETES ASSOC. - 0012-1797 .- 1939-327X. ; 66:7, s. 2019-2032
  • Tidskriftsartikel (refereegranskat)abstract
    • To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.
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21.
  • Nikpay, Majid, et al. (författare)
  • A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease
  • 2015
  • Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 47:10, s. 1121-1121
  • Tidskriftsartikel (refereegranskat)abstract
    • Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of similar to 185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.
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22.
  • Scepanovic, Petar, et al. (författare)
  • Human genetic variants and age are the strongest predictors of humoral immune responses to common pathogens and vaccines
  • 2018
  • Ingår i: Genome Medicine. - : Springer Science and Business Media LLC. - 1756-994X. ; 10:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Humoral immune responses to infectious agents or vaccination vary substantially among individuals, and many of the factors responsible for this variability remain to be defined. Current evidence suggests that human genetic variation influences (i) serum immunoglobulin levels, (ii) seroconversion rates, and (iii) intensity of antigen-specific immune responses. Here, we evaluated the impact of intrinsic (age and sex), environmental, and genetic factors on the variability of humoral response to common pathogens and vaccines. Methods: We characterized the serological response to 15 antigens from common human pathogens or vaccines, in an age- and sex-stratified cohort of 1000 healthy individuals (Milieu Intérieur cohort). Using clinical-grade serological assays, we measured total IgA, IgE, IgG, and IgM levels, as well as qualitative (serostatus) and quantitative IgG responses to cytomegalovirus, Epstein-Barr virus, herpes simplex virus 1 and 2, varicella zoster virus, Helicobacter pylori, Toxoplasma gondii, influenza A virus, measles, mumps, rubella, and hepatitis B virus. Following genome-wide genotyping of single nucleotide polymorphisms and imputation, we examined associations between ~5 million genetic variants and antibody responses using single marker and gene burden tests. Results: We identified age and sex as important determinants of humoral immunity, with older individuals and women having higher rates of seropositivity for most antigens. Genome-wide association studies revealed significant associations between variants in the human leukocyte antigen (HLA) class II region on chromosome 6 and anti-EBV and anti-rubella IgG levels. We used HLA imputation to fine map these associations to amino acid variants in the peptide-binding groove of HLA-DRβ1 and HLA-DPβ1, respectively. We also observed significant associations for total IgA levels with two loci on chromosome 2 and with specific KIR-HLA combinations. Conclusions: Using extensive serological testing and genome-wide association analyses in a well-characterized cohort of healthy individuals, we demonstrated that age, sex, and specific human genetic variants contribute to inter-individual variability in humoral immunity. By highlighting genes and pathways implicated in the normal antibody response to frequently encountered antigens, these findings provide a basis to better understand disease pathogenesis.
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23.
  • Sedlacek, Janosch, et al. (författare)
  • Evolutionary potential in the Alpine: trait heritabilities and performance variation of the dwarf willow Salix herbacea from different elevations and microhabitats
  • 2016
  • Ingår i: Ecology and Evolution. - : Wiley. - 2045-7758. ; 6:12, s. 3940-3952
  • Tidskriftsartikel (refereegranskat)abstract
    • Alpine ecosystems are seriously threatened by climate change. One of the key mechanisms by which plants can adapt to changing environmental conditions is through evolutionary change. However, we still know little about the evolutionary potential in wild populations of long-lived alpine plants. Here, we investigated heritabilities of phenological traits, leaf size, and performance traits in natural populations of the long-lived alpine dwarf shrub Salix herbacea using relatedness estimates inferred from SSR (Simple Sequence Repeat) markers. Salix herbacea occurs in early-and late-snowmelt microhabitats (ridges and snowbeds), and we assessed how performance consequences of phenological traits and leaf size differ between these microhabitats in order to infer potential for evolutionary responses. Salix herbacea showed low, but significant, heritabilities of leaf size, clonal and sexual reproduction, and moderate heritabilities of phenological traits. In both microhabitats, we found that larger leaves, longer intervals between snowmelt and leaf expansion, and longer GDD (growing-degree days) until leaf expansion resulted in a stronger increase in the number of stems (clonal reproduction). In snowbeds, clonal reproduction increased with a shorter GDD until flowering, while the opposite was found on ridges. Furthermore, the proportion of flowering stems increased with GDD until flowering in both microhabitats. Our results suggest that the presence of significant heritable variation in morphology and phenology might help S. herbacea to adapt to changing environmental conditions. However, it remains to be seen if the rate of such an evolutionary response can keep pace with the rapid rate of climate change.
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24.
  • Sedlacek, Janosch, et al. (författare)
  • The Response of the Alpine Dwarf Shrub Salix herbacea to Altered Snowmelt Timing : Lessons from a Multi-Site Transplant Experiment
  • 2015
  • Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:4
  • Tidskriftsartikel (refereegranskat)abstract
    • Climate change is altering spring snowmelt patterns in alpine and arctic ecosystems, and these changes may alter plant phenology, growth and reproduction. To predict how alpine plants respond to shifts in snowmelt timing, we need to understand trait plasticity, its effects on growth and reproduction, and the degree to which plants experience a home-site advantage. We tested how the common, long-lived dwarf shrub Salix herbacea responded to changing spring snowmelt time by reciprocally transplanting turfs of S. herbacea between early-exposure ridge and late-exposure snowbed microhabitats. After the transplant, we monitored phenological, morphological and fitness traits, as well as leaf damage, during two growing seasons. Salix herbacea leafed out earlier, but had a longer development time and produced smaller leaves on ridges relative to snowbeds. Longer phenological development times and smaller leaves were associated with reduced sexual reproduction on ridges. On snowbeds, larger leaves and intermediate development times were associated with increased clonal reproduction. Clonal and sexual reproduction showed no response to altered snowmelt time. We found no home-site advantage in terms of sexual and clonal reproduction. Leaf damage probability depended on snowmelt and thus exposure period, but had no short-term effect on fitness traits. We conclude that the studied populations of S. herbacea can respond to shifts in snowmelt by plastic changes in phenology and leaf size, while maintaining levels of clonal and sexual reproduction. The lack of a home-site advantage suggests that S. herbacea may not be adapted to different microhabitats. The studied populations are thus unlikely to react to climate change by rapid adaptation, but their responses will also not be constrained by small-scale local adaptation. In the short term, snowbed plants may persist due to high stem densities. However, in the long term, reduction in leaf size and flowering, a longer phenological development time and increased exposure to damage may decrease overall performance of S. herbacea under earlier snowmelt.
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25.
  • Stitziel, Nathan O., et al. (författare)
  • Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease
  • 2016
  • Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 374:12, s. 1134-1144
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND The discovery of low-frequency coding variants affecting the risk of coronary artery disease has facilitated the identification of therapeutic targets. METHODS Through DNA genotyping, we tested 54,003 coding-sequence variants covering 13,715 human genes in up to 72,868 patients with coronary artery disease and 120,770 controls who did not have coronary artery disease. Through DNA sequencing, we studied the effects of loss-of-function mutations in selected genes. RESULTS We confirmed previously observed significant associations between coronary artery disease and low-frequency missense variants in the genes LPA and PCSK9. We also found significant associations between coronary artery disease and low-frequency missense variants in the genes SVEP1 (p.D2702G; minor-allele frequency, 3.60%; odds ratio for disease, 1.14; P = 4.2x10(-10)) and ANGPTL4 (p.E40K; minor-allele frequency, 2.01%; odds ratio, 0.86; P = 4.0x10(-8)), which encodes angiopoietin-like 4. Through sequencing of ANGPTL4, we identified 9 carriers of loss-of-function mutations among 6924 patients with myocardial infarction, as compared with 19 carriers among 6834 controls (odds ratio, 0.47; P = 0.04); carriers of ANGPTL4 loss-of-function alleles had triglyceride levels that were 35% lower than the levels among persons who did not carry a loss-of-function allele (P = 0.003). ANGPTL4 inhibits lipoprotein lipase; we therefore searched for mutations in LPL and identified a loss-of-function variant that was associated with an increased risk of coronary artery disease (p.D36N; minor-allele frequency, 1.9%; odds ratio, 1.13; P = 2.0x10(-4)) and a gain-of-function variant that was associated with protection from coronary artery disease (p.S447*; minor-allele frequency, 9.9%; odds ratio, 0.94; P = 2.5x10(-7)). CONCLUSIONS We found that carriers of loss-of-function mutations in ANGPTL4 had triglyceride levels that were lower than those among noncarriers; these mutations were also associated with protection from coronary artery disease.
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26.
  • Surakka, Ida, et al. (författare)
  • The impact of low-frequency and rare variants on lipid levels.
  • 2015
  • Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 47:6, s. 589-597
  • Tidskriftsartikel (refereegranskat)abstract
    • Using a genome-wide screen of 9.6 million genetic variants achieved through 1000 Genomes Project imputation in 62,166 samples, we identify association to lipid traits in 93 loci, including 79 previously identified loci with new lead SNPs and 10 new loci, 15 loci with a low-frequency lead SNP and 10 loci with a missense lead SNP, and 2 loci with an accumulation of rare variants. In six loci, SNPs with established function in lipid genetics (CELSR2, GCKR, LIPC and APOE) or candidate missense mutations with predicted damaging function (CD300LG and TM6SF2) explained the locus associations. The low-frequency variants increased the proportion of variance explained, particularly for low-density lipoprotein cholesterol and total cholesterol. Altogether, our results highlight the impact of low-frequency variants in complex traits and show that imputation offers a cost-effective alternative to resequencing.
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27.
  • Webb, Thomas R., et al. (författare)
  • Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease
  • 2017
  • Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 69:7, s. 823-836
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits.OBJECTIVES This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci.METHODS In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs.RESULTS We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 x 10(-4) with a range of other diseases/traits.CONCLUSIONS We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk.
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28.
  • Brambila-Macias, Sergio Andres, 1980-, et al. (författare)
  • Interdisciplinary Insights Found for Product/Service System Design
  • 2016
  • Ingår i: DS 84: PROCEEDINGS OF THE DESIGN 2016 14TH INTERNATIONAL DESIGN CONFERENCE, VOLS 1-4. - : The Design Society. ; , s. 137-144
  • Konferensbidrag (refereegranskat)abstract
    • Product/Service System (PSS) is a different way of fulfilling customer needs by providing a bundle of products and services. PSS is by nature an interdisciplinary field of research that needs collaboration across disciplines. This research paper investigates how much interdisciplinary research has been carried in terms of insights used between two important disciplines, namely, Engineering Design and Industrial Marketing. The results show that few insights have been used across disciplines which shows a gap for further research.
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29.
  • Brouwer-Brolsma, Elske M., et al. (författare)
  • Combining traditional dietary assessment methods with novel metabolomics techniques: Present efforts by the Food Biomarker Alliance
  • 2017
  • Ingår i: Proceedings of the Nutrition Society. - 0029-6651 .- 1475-2719. ; 76:4, s. 619-627
  • Tidskriftsartikel (refereegranskat)abstract
    • FFQ, food diaries and 24 h recall methods represent the most commonly used dietary assessment tools in human studies on nutrition and health, but food intake biomarkers are assumed to provide a more objective reflection of intake. Unfortunately, very few of these biomarkers are sufficiently validated. This review provides an overview of food intake biomarker research and highlights present research efforts of the Joint Programming Initiative 'A Healthy Diet for a Healthy Life' (JPI-HDHL) Food Biomarkers Alliance (FoodBAll). In order to identify novel food intake biomarkers, the focus is on new food metabolomics techniques that allow the quantification of up to thousands of metabolites simultaneously, which may be applied in intervention and observational studies. As biomarkers are often influenced by various other factors than the food under investigation, FoodBAll developed a food intake biomarker quality and validity score aiming to assist the systematic evaluation of novel biomarkers. Moreover, to evaluate the applicability of nutritional biomarkers, studies are presently also focusing on associations between food intake biomarkers and diet-related disease risk. In order to be successful in these metabolomics studies, knowledge about available electronic metabolomics resources is necessary and further developments of these resources are essential. Ultimately, present efforts in this research area aim to advance quality control of traditional dietary assessment methods, advance compliance evaluation in nutritional intervention studies, and increase the significance of observational studies by investigating associations between nutrition and health.
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30.
  • Brunk, Elizabeth, et al. (författare)
  • Recon3D enables a three-dimensional view of gene variation in human metabolism
  • 2018
  • Ingår i: Nature Biotechnology. - : Springer Science and Business Media LLC. - 1087-0156 .- 1546-1696. ; 36:3, s. 272-281
  • Tidskriftsartikel (refereegranskat)abstract
    • Genome-scale network reconstructions have helped uncover the molecular basis of metabolism. Here we present Recon3D, a computational resource that includes three-dimensional (3D) metabolite and protein structure data and enables integrated analyses of metabolic functions in humans. We use Recon3D to functionally characterize mutations associated with disease, and identify metabolic response signatures that are caused by exposure to certain drugs. Recon3D represents the most comprehensive human metabolic network model to date, accounting for 3,288 open reading frames (representing 17% of functionally annotated human genes), 13,543 metabolic reactions involving 4,140 unique metabolites, and 12,890 protein structures. These data provide a unique resource for investigating molecular mechanisms of human metabolism. Recon3D is available at http://vmh.life.
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31.
  • Cortés, Andrés J., 1989- (författare)
  • On The Big Challenges of a Small Shrub : Ecological Genetics of Salix herbacea L
  • 2015
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • The response of plants to climate change is among the main questions in ecology and evolution. Faced with changing conditions, populations may respond by adapting, going extinct or migrating. Fine-scale environmental variation offers a unique mosaic to explore these alternatives. In this thesis, I used ecological surveys, field experiments and molecular methods to study the range of possible responses at a very local scale in the alpine dwarf willow Salix herbacea L. Since gene flow may impact the potential for adaptation and migration, I first explored whether phenological divergence driven by snowmelt patterns impacts gene flow. I found that sites with late snowmelt work as sinks of the genetic diversity, as compared to sites with early snowmelt. I also used a combined approach that looked at the selection, heritability and genomic architecture of ecologically-relevant traits, as well as genomic divergence across the snowmelt mosaic. In this way, I was able to understand which genomic regions may relate to phenological, growth and fitness traits, and which regions in the genome harbor genetic variation associated with late- and early- snowmelt sites. I found that most of the genomic divergence driven by snowmelt is novel and is localized in few regions. Also, Salix herbacea has a strong female bias. Sex bias may matter for adaptation to climate change because different sexes of many dioecious species differ in several functions that may fluctuate with changing conditions. I found that the bias is uniform across environments and is already present at seeds and seedlings. A polygenic sex determination system together with transmission distortion may be maintaining the bias. Overall, fast-evolving microhabitat-driven genomic divergence and, at the same time, genetically-based trait variation at a larger scale may play a role for the ability of S. herbacea to persist in diverse and variable conditions.
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32.
  • Crossfield, Ian J. M., et al. (författare)
  • 197 CANDIDATES AND 104 VALIDATED PLANETS IN K2's FIRST FIVE FIELDS
  • 2016
  • Ingår i: Astrophysical Journal Supplement Series. - : American Astronomical Society. - 0067-0049 .- 1538-4365. ; 226:1
  • Tidskriftsartikel (refereegranskat)abstract
    • We present 197 planet candidates discovered using data from the first year of the NASA K2 mission (Campaigns 0-4), along with the results of an intensive program of photometric analyses, stellar spectroscopy, high-resolution imaging, and statistical validation. We distill these candidates into sets of 104 validated planets (57 in multi-planet systems), 30 false positives, and 63 remaining candidates. Our validated systems span a range of properties, with median values of R-P = 2.3 R-circle plus, P = 8.6 days, T-eff = 5300 K, and Kp = 12.7 mag. Stellar spectroscopy provides precise stellar and planetary parameters for most of these systems. We show that K2 has increased by 30% the number of small planets known to orbit moderately bright stars (1-4 R-circle plus, Kp = 9-13. mag). Of particular interest are 76 planets smaller than 2 R-circle plus, 15 orbiting stars brighter than Kp = 11.5. mag, 5 receiving Earth-like irradiation levels, and several multi-planet systems-including 4 planets orbiting the M dwarf K2-72 near mean-motion resonances. By quantifying the likelihood that each candidate is a planet we demonstrate that our candidate sample has an overall false positive rate of 15%-30%, with rates substantially lower for small candidates (<2 R-circle plus) and larger for candidates with radii >8 R-circle plus and/or with P < 3 days. Extrapolation of the current planetary yield suggests that K2 will discover between 500 and 1000 planets in its planned four-year mission, assuming sufficient follow-up resources are available. Efficient observing and analysis, together with an organized and coherent follow-up strategy, are essential for maximizing the efficacy of planet-validation efforts for K2, TESS, and future large-scale surveys.
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33.
  • de Andrés Prada, Roberto, 1990- (författare)
  • Pulsed laser deposition and nanofabrication of mesoscopic devices based on cuprates and manganites
  • 2019
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • This thesis explores the growth, the nano-fabrication and the study of the magneto-transport properties of Superconductor/Ferromagnet/Superconductor (SFS) structures from complex oxides such as the high Tc superconducting cuprate YBa2Cu3O7 (YBCO) and the ferromagnetic manganites La2/3Ca1/3MnO3 and La2/3Sr1/3MnO3 (LCMO and LSMO), deposited with the pulsed laser deposition (PLD) technique.The present work has been possible thanks to the collaboration between the “Magnetism and Superconductivity” Group at the University of Fribourg, in Switzerland, and the “Experimentell Kondenserade Materiens Fysik” Group at Stockholm University, in Sweden.Earlier, the two research groups in Fribourg and Stockholm had studied SFS structures from YBCO/LaMnO3/YBCO multilayers with 20 nm thick ferromagnetic and insulating LaMnO3 barriers, and obtained signs of an unconventional spin-triplet current across these structures. This finding motivated the present thesis work with a focus on two main aspects.Firstly, to explore other candidate materials suitable as barriers and optimise their growth conditions as to maintain a large ferromagnetic moment and thus a high spin polarisation of the charge carriers. Secondly, to study what happens when the thickness of the ferromagnetic and insulating LaMnO3 barrier is reduced well below 20 nm to enable larger supercurrents.It has been shown for a series of YBCO/LCMO multilayers that the ferromagnetic moment of LCMO depends critically on the PLD growth conditions as well as on the thickness and even structural details of the YBCO layer on which they are grown. Furthermore, a protocol has been established to grow heterostructures with strongly ferromagnetic manganite layers embedded in thick YBCO layers by optimising the PLD growth conditions and by substituting the bottom YBCO layer with a Co and Ca substituted version of YBCO that has a tetragonal structure (tYBCO) instead of the orthorhombic one of plain YBCO.Devices suitable for perpendicular magneto-transport measurements have been nano-fabricated from YBCO/manganite/YBCO multilayers with ~10 nm thick LCMO and LSMO layers as the F barriers. While no clear indications of a spin-triplet component of the superconducting order parameter have been obtained yet, a negative and hysteretic magneto-resistance has been observed that is indicative of a strong ferromagnetic order in the thin manganite barrier. The latter suggests a potential memory functionality of such structures that could be exploited in future spintronic memory devices.Moreover, devices have been fabricated on SFS structures with a reduced thickness of the LaMnO3 barrier of 10 nm and 5 nm. These samples were grown prior to the beginning of this PhD work using non optimised growth conditions, and it was found that the ferromagnetic properties of these LaMnO3 barriers are strongly deteriorated. It remains to be seen whether the ferromagnetic order of such thin LaMnO3 layers can be also recovered by using the optimised growth conditions as for LSMO and LCMO.
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34.
  • de Vries, Paul S., et al. (författare)
  • Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions
  • 2019
  • Ingår i: American Journal of Epidemiology. - : Oxford University Press. - 0002-9262 .- 1476-6256. ; 188:6, s. 1033-1054
  • Tidskriftsartikel (refereegranskat)abstract
    • A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2-degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 x 10(-6)) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 x 10(-8) using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models.
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35.
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36.
  • Engert, Andreas, et al. (författare)
  • The European Hematology Association Roadmap for European Hematology Research : a consensus document
  • 2016
  • Ingår i: Haematologica. - Pavia, Italy : Ferrata Storti Foundation (Haematologica). - 0390-6078 .- 1592-8721. ; 101:2, s. 115-208
  • Tidskriftsartikel (refereegranskat)abstract
    • The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at (sic)23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap. The EHA Roadmap identifies nine 'sections' in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders. The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients.
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37.
  • Evangelou, Evangelos, et al. (författare)
  • Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.
  • 2018
  • Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:10, s. 1412-1425
  • Tidskriftsartikel (refereegranskat)abstract
    • High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.
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38.
  • Feitosa, Mary F., et al. (författare)
  • Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries
  • 2018
  • Ingår i: PLOS ONE. - : Public library science. - 1932-6203. ; 13:6
  • Tidskriftsartikel (refereegranskat)abstract
    • Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in approximate to 131 K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P <1.0 x 10(-5)). In Stage 2, these SNVs were tested for independent external replication in individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10(-8)). For African ancestry samples, we detected 18 potentially novel BP loci (P< 5.0 x 10(-8)) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2 have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.
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39.
  • Frazier-Wood, Alexis C., et al. (författare)
  • Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses
  • 2016
  • Ingår i: Nature Genetics. - : Nature Research (part of Springer Nature). - 1061-4036 .- 1546-1718. ; 48, s. 624-
  • Tidskriftsartikel (refereegranskat)abstract
    • Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (vertical bar(p) over cap vertical bar approximate to 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.
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40.
  • Freyschlag, Christian F, et al. (författare)
  • Imaging practice in low-grade gliomas among European specialized centers and proposal for a minimum core of imaging.
  • 2018
  • Ingår i: Journal of Neuro-Oncology. - : Springer Science and Business Media LLC. - 0167-594X .- 1573-7373. ; 139:3, s. 699-711
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: Imaging studies in diffuse low-grade gliomas (DLGG) vary across centers. In order to establish a minimal core of imaging necessary for further investigations and clinical trials in the field of DLGG, we aimed to establish the status quo within specialized European centers.METHODS: An online survey composed of 46 items was sent out to members of the European Low-Grade Glioma Network, the European Association of Neurosurgical Societies, the German Society of Neurosurgery and the Austrian Society of Neurosurgery.RESULTS: A total of 128 fully completed surveys were received and analyzed. Most centers (n = 96, 75%) were academic and half of the centers (n = 64, 50%) adhered to a dedicated treatment program for DLGG. There were national differences regarding the sequences enclosed in MRI imaging and use of PET, however most included T1 (without and with contrast, 100%), T2 (100%) and TIRM or FLAIR (20, 98%). DWI is performed by 80% of centers and 61% of centers regularly performed PWI.CONCLUSION: A minimal core of imaging composed of T1 (w/wo contrast), T2, TIRM/FLAIR, PWI and DWI could be identified. All morphologic images should be obtained in a slice thickness of ≤ 3 mm. No common standard could be obtained regarding advanced MRI protocols and PET.IMPORTANCE OF THE STUDY: We believe that our study makes a significant contribution to the literature because we were able to determine similarities in numerous aspects of LGG imaging. Using the proposed "minimal core of imaging" in clinical routine will facilitate future cooperative studies.
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41.
  • Frigoli, Enrico, et al. (författare)
  • Design and rationale of the Management of High Bleeding Risk Patients Post Bioresorbable Polymer Coated Stent Implantation With an Abbreviated Versus Standard DAPT Regimen (MASTER DAPT) Study
  • 2019
  • Ingår i: American Heart Journal. - : MOSBY-ELSEVIER. - 0002-8703 .- 1097-6744. ; 209, s. 97-105
  • Tidskriftsartikel (refereegranskat)abstract
    • Background The optimal duration of antiplatelet therapy in high-bleeding risk (HBR) patients with coronary artery disease treated with newer-generation drug-eluting bioresorbable polymer-coated stents remains unclear. Design MASTER DAPT (clinicaltrial.gov NCT03023020) is an investigator-initiated, open-label, multicenter, randomized controlled trial comparing an abbreviated versus a standard duration of antiplatelet therapy after bioresorbable polymer-coated Ultimaster (TANSEI) sirolimus-eluting stent implantation in approximately 4,300 HBR patients recruited from >= 100 interventional cardiology centers globally. After a mandatory 30-day dual-antiplatelet therapy (DAPT) run-in phase, patients are randomized to (a) a single antiplatelet regimen until study completion or up to 5 months in patients with clinically indicated oral anticoagulation (experimental 1-month DAPT group) or (b) continue DAPT for at least 5 months in patients without or 2 in patients with concomitant indication to oral anticoagulation, followed by a single antiplatelet regimen (standard antipkitelet regimen). With a final sample size of 4,300 patients, this study is powered to assess the noninferiority of the abbreviated antiplatelet regimen with respect to the net adverse clinical and major adverse cardiac and cerebral events composite end points and if satisfied for the superiority of abbreviated as compared to standard antiplatelet therapy duration in terms of major or clinically relevant nonmajor bleeding. Study end points will be adjudicated by a blinded Clinical Events Committee. Conclusions The MASTER DAPT study is the first randomized controlled trial aiming at ascertaining the optimal duration of antiplatelet therapy in HBR patients treated with sirolimus-eluting bioresorbable polymer-coated stent implantation.
  •  
42.
  • Glazunov, Andres Alayon, 1969, et al. (författare)
  • Reverberating Dreams - the Story of an OTA Chamber
  • 2017
  • Ingår i: 2017 IEEE INTERNATIONAL SYMPOSIUM ON ANTENNAS AND PROPAGATION & USNC/URSI NATIONAL RADIO SCIENCE MEETING. - 1522-3965. - 9781538632840 ; 2017-January, s. 239-240
  • Konferensbidrag (refereegranskat)abstract
    • By the late 90's Prof. Per-Simon Kildal came to the insight that reverberation chambers could be useful tools for characterizing small antennas and wireless devices in multipath channels. This was a revolutionizing idea that was not so well received at first. However, with perseverance, he worked through the challenges to see his dream become a reality. This paper is to recognize Prof. Kildal's contributions carried out at Chalmers, the spin-off company Bluetest, but also the contributions of many other people that have been key to materializing his dream.
  •  
43.
  • Headley, Alison, et al. (författare)
  • Neurogranin as a predictor of memory and executive function decline in MCI patients.
  • 2018
  • Ingår i: Neurology. - 1526-632X. ; 90:10
  • Tidskriftsartikel (refereegranskat)abstract
    • To determine whether high CSF levels of neurogranin (Ng) predict longitudinal decline in memory and executive function during early-stage Alzheimer disease (AD).Baseline levels of CSF Ng were studied in relation to cross-sectional and longitudinal cognitive performance over 8 years. Data were obtained from the Alzheimer's Disease Neuroimaging Initiative database, and participants with normal cognition (n = 111) and mild cognitive impairment (MCI) (n = 193) were included.High levels of CSF Ng were associated with poor baseline memory scores (β = -0.21,p< 0.0001). CSF Ng predicted both memory and executive function decline over time (β = -0.0313,p= 0.0068 and β = -0.0346,p= 0.0169, respectively) independently of age, sex, education, andAPOEε4 status. When the rate of decline by tertiles was examined, CSF Ng was a level-dependent predictor of memory function, whereby the group with highest levels of Ng showed the fastest rates of decline in both memory and executive function. When examined separately, elevated Ng was associated with cognitive decline in participants with MCI but not in those with normal cognition. The levels of CSF Ng were not associated with cognitive measures when tau and amyloid 42 (Aβ42) were controlled for in these analyses.High CSF Ng associates with poor memory scores in participants with MCI cross-sectionally and with poor memory and executive function longitudinally. The association of Ng with cognitive measures disappears when tau and Aβ42are included in the statistical models. Our findings suggest that CSF Ng may serve as a biomarker of cognition. Synaptic dysfunction contributes to cognitive impairment in early-stage AD.
  •  
44.
  • Hägg, Sara, et al. (författare)
  • Adiposity as a cause of cardiovascular disease : a Mendelian randomization study
  • 2015
  • Ingår i: International Journal of Epidemiology. - : Oxford University Press (OUP). - 0300-5771 .- 1464-3685. ; 44:2, s. 578-586
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Adiposity, as indicated by body mass index (BMI), has been associated with risk of cardiovascular diseases in epidemiological studies. We aimed to investigate if these associations are causal, using Mendelian randomization (MR) methods. Methods: The associations of BMI with cardiovascular outcomes [coronary heart disease (CHD), heart failure and ischaemic stroke], and associations of a genetic score (32 BMI single nucleotide polymorphisms) with BMI and cardiovascular outcomes were examined in up to 22 193 individuals with 3062 incident cardiovascular events from nine prospective follow-up studies within the ENGAGE consortium. We used random-effects meta-analysis in an MR framework to provide causal estimates of the effect of adiposity on cardiovascular outcomes. Results: There was a strong association between BMI and incident CHD (HR = 1.20 per SD-increase of BMI, 95% CI, 1.12-1.28, P = 1.9.10(-7)), heart failure (HR = 1.47, 95% CI, 1.35-1.60, P = 9.10(-19)) and ischaemic stroke (HR = 1.15, 95% CI, 1.06-1.24, P = 0.0008) in observational analyses. The genetic score was robustly associated with BMI (beta = 0.030 SD-increase of BMI per additional allele, 95% CI, 0.028-0.033, P = 3.10(-107)). Analyses indicated a causal effect of adiposity on development of heart failure (HR = 1.93 per SD-increase of BMI, 95% CI, 1.12-3.30, P = 0.017) and ischaemic stroke (HR = 1.83, 95% CI, 1.05-3.20, P = 0.034). Additional cross-sectional analyses using both ENGAGE and CARDIoGRAMplusC4D data showed a causal effect of adiposity on CHD. Conclusions: Using MR methods, we provide support for the hypothesis that adiposity causes CHD, heart failure and, previously not demonstrated, ischaemic stroke.
  •  
45.
  • Joshi, Peter K, et al. (författare)
  • Directional dominance on stature and cognition in diverse human populations
  • 2015
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 523:7561, s. 459-462
  • Tidskriftsartikel (refereegranskat)abstract
    • Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
  •  
46.
  • Karmin, Monika, et al. (författare)
  • A recent bottleneck of Y chromosome diversity coincides with a global change in culture.
  • 2015
  • Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 25:4
  • Tidskriftsartikel (refereegranskat)abstract
    • It is commonly thought that human genetic diversity in non-African populations was shaped primarily by an out-of-Africa dispersal 50-100 thousand yr ago (kya). Here, we present a study of 456 geographically diverse high-coverage Y chromosome sequences, including 299 newly reported samples. Applying ancient DNA calibration, we date the Y-chromosomal most recent common ancestor (MRCA) in Africa at 254 (95% CI 192-307) kya and detect a cluster of major non-African founder haplogroups in a narrow time interval at 47-52 kya, consistent with a rapid initial colonization model of Eurasia and Oceania after the out-of-Africa bottleneck. In contrast to demographic reconstructions based on mtDNA, we infer a second strong bottleneck in Y-chromosome lineages dating to the last 10 ky. We hypothesize that this bottleneck is caused by cultural changes affecting variance of reproductive success among males.
  •  
47.
  • Kato, Norihiro, et al. (författare)
  • Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation
  • 2015
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 47:11, s. 1282-1293
  • Tidskriftsartikel (refereegranskat)abstract
    • We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10−11 to 5.0 × 10−21). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10−6). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.
  •  
48.
  • Martin-Almedina, Silvia, et al. (författare)
  • EPHB4 kinase-inactivating mutations cause autosomal dominant lymphatic-related hydrops fetalis
  • 2016
  • Ingår i: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 126:8, s. 3080-3088
  • Tidskriftsartikel (refereegranskat)abstract
    • Hydrops fetalis describes fluid accumulation in at least 2 fetal compartments, including abdominal cavities, pleura, and pericardium, or in body tissue. The majority of hydrops fetalis cases are nonimmune conditions that present with generalized edema of the fetus, and approximately 15% of these nonimmune cases result from a lymphatic abnormality. Here, we have identified an autosomal dominant, inherited form of lymphatic-related (nonimmune) hydrops fetalis (LRHF). Independent exome sequencing projects on 2 families with a history of in utero and neonatal deaths associated with nonimmune hydrops fetalis uncovered 2 heterozygous missense variants in the gene encoding Eph receptor B4 (EPHB4). Biochemical analysis determined that the mutant EPHB4 proteins are devoid of tyrosine kinase activity, indicating that loss of EPHB4 signaling contributes to LRHF pathogenesis. Further, inactivation of Ephb4 in lymphatic endothelial cells of developing mouse embryos led to defective lymphovenous valve formation and consequent subcutaneous edema. Together, these findings identify EPHB4 as a critical regulator of early lymphatic vascular development and demonstrate that mutations in the gene can cause an autosomal dominant form of LRHF that is associated with a high mortality rate.
  •  
49.
  •  
50.
  • Patel, Riyaz S., et al. (författare)
  • Subsequent Event Risk in Individuals With Established Coronary Heart Disease : Design and Rationale of the GENIUS-CHD Consortium
  • 2019
  • Ingår i: Circulation. - 2574-8300. ; 12:4
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: The Genetics of Subsequent Coronary Heart Disease (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD.METHODS: The consortium currently includes 57 studies from 18 countries, recruiting 185 614 participants with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events.RESULTS: Enrollment into the individual studies took place between 1985 to present day with a duration of follow-up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (hazard ratio, 1.15; 95% CI, 1.14-1.16) per 5-year increase, male sex (hazard ratio, 1.17; 95% CI, 1.13-1.21) and smoking (hazard ratio, 1.43; 95% CI, 1.35-1.51) with risk of subsequent CHD death or myocardial infarction and differing associations with other individual and composite cardiovascular endpoints.CONCLUSIONS: GENIUS-CHD is a global collaboration seeking to elucidate genetic and nongenetic determinants of subsequent event risk in individuals with established CHD, to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators.
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