Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke

Genetic factors have been implicated in stroke risk but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) in ischemic stroke and its subtypes in 3,548 cases and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 cases and 6,281 controls. We replicated reported associations between variants close to PITX2 and ZFHX3 with cardioembolic stroke, and a 9p21 locus with large vessel stroke. We identified a novel association for a SNP within the histone deacetylase 9(HDAC9) gene on chromosome 7p21.1 which was associated with large vessel stroke including additional replication in a further 735 cases and 28583 controls (rs11984041, combined P = 1.87×10−11, OR=1.42 (95% CI) 1.28-1.57). All four loci exhibit evidence for heterogeneity of effect across the stroke subtypes, with some, and possibly all, affecting risk for only one subtype. This suggests differing genetic architectures for different stroke subtypes

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

Notable shifts beyond pre-industrial streamflow and soil moisture conditions transgress the planetary boundary for freshwater change

Human actions compromise the many life-supporting functions provided by the freshwater cycle. Yet, scientific understanding of anthropogenic freshwater change and its long-term evolution is limited. Here, using a multi-model ensemble of global hydrological models, we estimate how, over a 145-year industrial period (1861–2005), streamflow and soil moisture have deviated from pre-industrial baseline conditions (defined by 5th–95th percentiles, at 0.5° grid level and monthly timestep over 1661–1860). Comparing the two periods, we find an increased frequency of local deviations on ~45% of land area, mainly in regions under heavy direct or indirect human pressures. To estimate humanity’s aggregate impact on these two important elements of the freshwater cycle, we present the evolution of deviation occurrence at regional to global scales. Annually, local streamflow and soil moisture deviations now occur on 18.2% and 15.8% of global land area, respectively, which is 8.0 and 4.7 percentage points beyond the ~3 percentage point wide pre-industrial variability envelope. Our results signify a substantial shift from pre-industrial streamflow and soil moisture reference conditions to persistently increasing change. This indicates a transgression of the new planetary boundary for freshwater change, which is defined and quantified using our approach, calling for urgent actions to reduce human disturbance of the freshwater cycle

Notable shifts beyond pre-industrial streamflow and soil moisture conditions transgress the planetary boundary for freshwater change

Human actions compromise the many life-supporting functions provided by the freshwater cycle. Yet, scientific understanding of anthropogenic freshwater change and its long-term evolution is limited. Here, using a multi-model ensemble of global hydrological models, we estimate how, over a 145-year industrial period (1861–2005), streamflow and soil moisture have deviated from pre-industrial baseline conditions (defined by 5th–95th percentiles, at 0.5° grid level and monthly timestep over 1661–1860). Comparing the two periods, we find an increased frequency of local deviations on ~45% of land area, mainly in regions under heavy direct or indirect human pressures. To estimate humanity’s aggregate impact on these two important elements of the freshwater cycle, we present the evolution of deviation occurrence at regional to global scales. Annually, local streamflow and soil moisture deviations now occur on 18.2% and 15.8% of global land area, respectively, which is 8.0 and 4.7 percentage points beyond the ~3 percentage point wide pre-industrial variability envelope. Our results signify a substantial shift from pre-industrial streamflow and soil moisture reference conditions to persistently increasing change. This indicates a transgression of the new planetary boundary for freshwater change, which is defined and quantified using our approach, calling for urgent actions to reduce human disturbance of the freshwater cycle

Genetics of the thrombomodulin-endothelial cell protein C receptor system and the risk of early-onset ischemic stroke

Background and purpose Polymorphisms in coagulation genes have been associated with early-onset ischemic stroke. Here we pursue an a priori hypothesis that genetic variation in the endothelial-based receptors of the thrombomodulin-protein C system (THBD and PROCR) may similarly be associated with early-onset ischemic stroke. We explored this hypothesis utilizing a multi-tage design of discovery and replication. Methods Discovery was performed in the Genetics-of-Early-Onset Stroke (GEOS) Study, a biracial population-based case-control study of ischemic stroke among men and women aged 1549 including 829 cases of first ischemic stroke (42.2% African-American) and 850 age-comparable stroke-free controls (38.1% African-American). Twenty-four single-nucleotide-polymorphisms (SNPs) in THBD and 22 SNPs in PROCR were evaluated. Following LD pruning (r(2)>= 0.8), we advanced uncorrelated SNPs forward for association analyses. Associated SNPs were evaluated for replication in an early-onset ischemic stroke population (onset-ge Results Among GEOS Caucasians, PROCR rs9574, which was in strong LD with 8 other SNPs, and one additional independent SNP rs2069951, were significantly associated with ischemic stroke (rs9574, OR = 1.33, p = 0.003; rs2069951, OR = 1.80, p = 0.006) using an additive-model adjusting for age, gender and population-structure. Adjusting for risk factors did not change the associations; however, associations were strengthened among those without risk factors. PROCR rs9574 also associated with early-onset ischemic stroke in the replication sample (OR = 1.08, p = 0.015), but not older-onset stroke. There were no PROCR associations in African-Americans, nor were there any THBD associations in either ethnicity. Conclusion PROCR polymorphisms are associated with early-onset ischemic stroke in Caucasians.Peer reviewe

Commitment zu aktivem Daten- und -softwaremanagement in großen Forschungsverbünden

Wir erkennen die Wichtigkeit von Forschungsdaten und -software für unsere Forschungsprozesse an und ordnen die Veröffentlichung von Forschungsdaten und -software als wesentlichen Bestandteil der wissenschaftlichen Publikationstätigkeit ein. Dafür unterstützen wir als Verbund unsere Forschenden im Umgang mit Daten und Software nach den FAIR-Prinzipien in Einvernehmen mit dem DFG-Kodex “Leitlinien zur Sicherung guter wissenschaftlicher Praxis”. In Zusammenarbeit mit unseren Institutionen und Fachcommunities stellen wir adäquate Forschungsdatenmanagement-Werkzeuge und -Dienste bereit und befähigen unsere Forschenden zum Umgang damit. Dabei bauen wir vorzugsweise auf existierenden Angeboten auf und bemühen uns im Gegenzug um deren Anpassung an unsere Bedürfnisse. Wir streben Maßnahmen für die Definition und Sicherstellung der Qualität unserer Forschungsdaten und -software an. Wir verwenden vorzugsweise existierende Daten-/Metadatenstandards und vernetzen uns nach Möglichkeit für die Erstellung und Implementierung neuer Standards mit entsprechenden nationalen und internationalen Initiativen. Wir verfolgen die Entwicklungen im Bereich des Forschungsdaten- und -softwaremanagements und prüfen neu entstehende Empfehlungen und Richtlinien zeitnah auf ihre Umsetzbarkeit

Contribution of Common Genetic Variants to Risk of Early-Onset Ischemic Stroke

Background and Objectives Current genome-wide association studies of ischemic stroke have focused primarily on late-onset disease. As a complement to these studies, we sought to identify the contribution of common genetic variants to risk of early-onset ischemic stroke. Methods We performed a meta-analysis of genome-wide association studies of early-onset stroke (EOS), ages 18-59 years, using individual-level data or summary statistics in 16,730 cases and 599,237 nonstroke controls obtained across 48 different studies. We further compared effect sizes at associated loci between EOS and late-onset stroke (LOS) and compared polygenic risk scores (PRS) for venous thromboembolism (VTE) between EOS and LOS. Results We observed genome-wide significant associations of EOS with 2 variants in ABO, a known stroke locus. These variants tag blood subgroups O1 and A1, and the effect sizes of both variants were significantly larger in EOS compared with LOS. The odds ratio (OR) for rs529565, tagging O1, was 0.88 (95% confidence interval [CI]: 0.85-0.91) in EOS vs 0.96 (95% CI: 0.92-1.00) in LOS, and the OR for rs635634, tagging A1, was 1.16 (1.11-1.21) for EOS vs 1.05 (0.99-1.11) in LOS; p-values for interaction = 0.001 and 0.005, respectively. Using PRSs, we observed that greater genetic risk for VTE, another prothrombotic condition, was more strongly associated with EOS compared with LOS (p = 0.008). Discussion The ABO locus, genetically predicted blood group A, and higher genetic propensity for venous thrombosis are more strongly associated with EOS than with LOS, supporting a stronger role of prothrombotic factors in EOS.Peer reviewe

52 Genetic Loci Influencing Myocardial Mass.

BACKGROUND: Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death. OBJECTIVES: This meta-analysis sought to gain insights into the genetic determinants of myocardial mass. METHODS: We carried out a genome-wide association meta-analysis of 4 QRS traits in up to 73,518 individuals of European ancestry, followed by extensive biological and functional assessment. RESULTS: We identified 52 genomic loci, of which 32 are novel, that are reliably associated with 1 or more QRS phenotypes at p < 1 × 10(-8). These loci are enriched in regions of open chromatin, histone modifications, and transcription factor binding, suggesting that they represent regions of the genome that are actively transcribed in the human heart. Pathway analyses provided evidence that these loci play a role in cardiac hypertrophy. We further highlighted 67 candidate genes at the identified loci that are preferentially expressed in cardiac tissue and associated with cardiac abnormalities in Drosophila melanogaster and Mus musculus. We validated the regulatory function of a novel variant in the SCN5A/SCN10A locus in vitro and in vivo. CONCLUSIONS: Taken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe