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 ancestry(1,2). 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 analysis(3), 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 approach(4), 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 ancestry(5). 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.</p

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

Dirt or Antibiotic RH1?

In our microbiology lab class we are attempting to find an antibiotic. Antibiotics are starting to become more resistant. More people are now dying from diseases that used to be treatable. The hope of this project is to find a new antibiotic that is not resistant and will be able to kill the disease inside someone. We are working with a group called Small World Initiatives. A lot of microbes and bacteria are found in the dirt, so I collected dirt from my front yard. I diluted this dirt to get a dirt and water mixture where I can get countable microbes. I plated my mixture onto petri dishes and let them incubate to see what would grow. I looked for special areas on the plates to see if there were any individual species that would not grow next to another because those are possible bacteria that can lead to an antibiotic. I picked out around 12 colonies that looked promising and put them on a new petri dish to grow each one again and incubate it. My species RH1 was tested against Bacillus subtilis and the two did not grow together. Further testing to identify RH1 is done to continue the experiment in seeing if it is able to produce an antibiotic or if it is just an average microbe from the dirt

IFNgamma differentially controls the development of idiopathic pneumonia syndrome and GVHD of the gastrointestinal tract

Copyright © 2007 by American Society of HematologyAlthough proinflammatory cytokines are key mediators of tissue damage during graft-versus-host disease (GVHD), IFNgamma has previously been attributed with both protective and pathogenic effects. We have resolved this paradox by using wild-type (wt), IFNgamma(-/-), and IFNgammaR(-/-) mice as donors or recipients in well-described models of allogeneic stem cell transplantation (SCT). We show that donor-derived IFNgamma augments acute GVHD via direct effects on (1) the donor T cell to promote T helper 1 (Th1) differentiation and (2) the gastrointestinal (GI) tract to augment inflammatory cytokine generation. However, these detrimental effects are overwhelmed by a protective role of IFNgamma in preventing the development of idiopathic pneumonia syndrome (IPS). This is the result of direct effects on pulmonary parenchyma to prevent donor cell migration and expansion within the lung. Thus, IFNgamma is the key cytokine differentially controlling the development of IPS and gastrointestinal GVHD after allogeneic SCT.Angela C. Burman, Tatjana Banovic, Rachel D. Kuns, Andrew D. Clouston, Amanda C. Stanley, Edward S. Morris, Vanessa Rowe, Helen Bofinger, Renae Skoczylas, Neil Raffelt, Olivier Fahy, Shaun R. McColl, Christian R. Engwerda, Kelli P. A. McDonald, and Geoffrey R. Hil

label, code and description lookup table for class hierarchy

<p>A table permitting lookup for BENTHOZ-2015 between Squidle codes, plain text descriptions, and CAAB codes.</p

Mapping from regional CPC code to CATAMI hierarchy

<p>Files indicating how class codes from different regions were mapped to the classes in the CATAMI hierarchical classification scheme for BENTHOZ-2015.</p

BENTHOZ-2015 private data set (hidden labels)

<p>The private part of the BENTHOZ-2015 Australian benthic imagery data set, with expert labels hidden (but location and other metadata provided). Contact authors to compare results of algorithms against this data set.The private part of the BENTHOZ-2015 Australian benthic imagery data set, with expert labels hidden (but location and other metadata provided). Contact authors to compare results of algorithms against this data set.</p