Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries

Startbijeenkomst WCM

Startbijeenkomst WC

Biomethane from hydrogen and carbon dioxide

The project BioP2M came to a close in June 2019 after a consortium of stakeholders in the field of energy transition worked together to research the diverse role of Methane. In this report the results are presented and future plans are discussed

Measurement of the Vector and Tensor Asymmetries at Large Missing Momentum in Quasielastic ([→ over e],e′p) Electron Scattering from Deuterium

We report the measurement of the beam-vector and tensor asymmetries A[subscript ed][superscript V] and A[subscript d][superscript T] in quasielastic ([→ over e],e′p) electrodisintegration of the deuteron at the MIT-Bates Linear Accelerator Center up to missing momentum of 500  MeV/c. Data were collected simultaneously over a momentum transfer range 0.1<Q[superscript 2]<0.5  (GeV/c)[superscript 2] with the Bates Large Acceptance Spectrometer Toroid using an internal deuterium gas target polarized sequentially in both vector and tensor states. The data are compared with calculations. The beam-vector asymmetry A[subscript ed][superscript V] is found to be directly sensitive to the D-wave component of the deuteron and has a zero crossing at a missing momentum of about 320  MeV/c, as predicted. The tensor asymmetry A[subscript d][superscript T] at large missing momentum is found to be dominated by the influence of the tensor force in the neutron-proton final-state interaction. The new data provide a strong constraint on theoretical models

Publisher Correction: Economic evaluation of operative versus nonoperative treatment of a humeral shaft fracture: economic analyses alongside a multicenter prospective cohort study (HUMMER) (European Journal of Trauma and Emergency Surgery, (2022), 10.1007/s00068-022-02160-1)

In this article, the order that the authors appeared in the author list was incorrect. The correct order is: Saskia H. Van Bergen1 · Esther M. M. Van Lieshout1 · Kiran C. Mahabier1 · Alexandra J. L. M. Geraerds2 · Suzanne Polinder2 · Dennis Den Hartog1 · Michael H. J. Verhofstad1 · on behalf of the HUMMER Investigators