Open Targets

Out now on bioRxiv! Caia Dominicus, Diego Peretti, Geraldine Rodschinka, and Sam Ogden perform the first systematic functional characterisation of knockout of ~250 genes associated with Alzheimer's disease. Read the paper: doi.org/10.64898/202...

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Their model system can recapitulate gene programmes that are altered during disease progression, and nominates potential therapeutic candidates by identifying knockouts that influence these programmes.

For example, they explore CCDC6, a poorly understood gene recently identified through GWAS, for which knockout had a specific effect in iAstrocytes on cell cycle, mitochondrial stress and activation state. Find out more: doi.org/10.64898/202...

By combining single cell transcriptomics with five phenotypic readouts in iNeurons and iAstrocytes, they found that the perturbation of different disease-associated genes converged on a set of highly cell type-specific transcriptional programmes and phenotypic signatures.

Out now in Drug Discovery Today! A team at Open Targets review pathway-driven target prioritisation in drug discovery, and present a practical framework to combine pathway evidence with genomic data in early-stage prioritisation www.sciencedirect.com/science/arti...

Open Targets reposted

Saez-Rodriguez Group

@saezlab.bsky.social

7 Sept

🧵 Introducing Karenina, an open-source framework to evaluate LLMs & agents: doi.org/10.64898/202...

The Open Targets Platform autumn (26.09) release is out now! 🍂 It's packed with genetics updates, with: 🧬 1.24 million new molecular QTL credible sets 🧬 2 new sources of gene burden data 🧬 Updates from the GWAS Catalog 🧬 Genetic constraint data for X- and Y-linked genes through gnomAD and more!

12 Aug

Ambitious science can start in the most unglamorous places. In 2015, gastroenterologist Tim Raine and geneticist Carl Anderson had a casual conversation in an underground carpark, which led to the largest single-cell dataset of Inflammatory Bowel Disease (IBD)-relevant tissues

12 Aug

After persuading funding bodies—Open Targets, the @sangerinstitute.bsky.social, and the Crohn’s and Colitis Foundation—that this was worth the gamble, they launched the “IBDverse”, and processed almost 1200 samples from over 600 patients. Nothing on this scale had ever been attempted before.

blog.opentargets.orgOrigins of the IBDverse: how a conversation in a carpark became one of the largest gut cell studiesIn 2015, Tim Raine and Carl Anderson had the ambitious idea of using single-cell sequencing to gain insights into the genes and cell types causally driving Inflammatory Bowel Disease (IBD), a project ...

12 Aug

This work, the largest study of its kind, was recently published in Nature and Nature Genetics. Find out more about the origins of the IBDverse on the blog: blog.opentargets.org/origins-of-t...

4 Aug

6 years 646 patients 1193 samples 100 endoscopists 9 lab scientists 3 postdocs 2 PhD students 502 courier runs from Addenbrooke’s Hospital to @sangerinstitute.bsky.social IBDverse is the largest single-cell dataset of Inflammatory Bowel Disease (IBD)—and generating the data for it was no mean feat

youtu.beBuilding the IBDverse: the science and team behind a landmark study of inflammatory bowel diseaseYouTube video by Open Targets

4 Aug

We talked to Menatallah Ghouraba, Rebecca McIntyre, and Cristina Cotobal Martin to get a behind-the-scenes perspective on the project. The IBDverse was a collaboration between Open Targets, the Wellcome Sanger Institute, and @cuh.nhs.uk Watch the whole story on YouTube: youtu.be/Hy0eqTiZtr0

fg.bmj.comPatient and public involvement and engagement in research: who, why, when and how to get it rightPatient and public involvement and engagement (PPIE) refers to the different ways those with lived experience, including patients, family, friends and carers, and the public engage with the design, de...

28 July

"Patients know what it’s like to live with these conditions on a daily basis and the impact it has on our lives. By getting involved, we can help clinicians and researchers understand what really matters to us, so future research and treatments genuinely meet our needs." fg.bmj.com/content/earl...

The Open-IBD project team present the key role that PPIE has played in their longitudinal study of inflammatory bowel disease (IBD), its impact on the members of the Lived Experience Advisory Panel (quoted here) and the research team.

28 July

"Being involved with the Open-IBD study has been a fantastic experience. The research team have been welcoming and responsive, not only listening to our suggestions and experiences, but also making tangible changes to the project based on our input."

Patient and public involvement and engagement (PPIE) has become a fundamental part of scientific research, improving the relevance and quality of the work. But who should you involve in PPIE? At what stage of the project should you involve them, and how?

nature.comA data-driven framework reconstructs the molecular continuum of human MASLD progression - Nature MetabolismA trajectory-based molecular framework reveals coordinated temporal shifts in metabolic, inflammatory and fibrogenic mechanisms across the human MASLD spectrum.

21 July

“We hope our framework will help drive a conceptual shift in how MASLD is studied and understood.” A new study reframes Metabolic dysfunction-Associated Steatotic Liver Disease as a continuous process, better capturing the underlying disease biology www.nature.com/articles/s42...

In parallel, they used a histology-based patient ranking to stratify patients into sequential overlapping groups, to capture the continuous trajectory of the disease.

21 July

This provides a starting point to deciphering the mechanisms that underpin MASLD, which could lead to better treatments and diagnosis of patients. Their approach could be applied to similar diseases where access to longitudinal data is challenging www.nature.com/articles/s42...

Published in Nature Metabolism, the study establishes a methodology to integrate multi-modal MASLD patient data, by anchoring changes in gene expression to the histological changes that characterise MASLD progression and are common to all patients

21 July

Using this methodology, the team created a MASLD-related regulatory network that captures both signalling pathway activities and cellular response patterns.

14 July

Out now in Nature Metabolism! 🖥️🧬 An Open Targets project has identified a set of plasma proteins that could be used to diagnose and monitor patients with Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) www.nature.com/articles/s42...

Their method anchors changes in gene expression to the histological changes that characterise MASLD progression and are common to all patients. This work reframes MASLD as a continuous process rather than a series of distinct disease stages.

14 July

From this, they found 57 genes that could be measured in the blood and used to predict where patients are in the disease trajectory This biomarker panel outperformed current non-invasive diagnostic tests, and could complement and refine existing tests, or pending validation, replace them Congrats!

Previously known as non-alcoholic fatty liver disease, MASLD is one of the leading causes of chronic liver dysfunction worldwide, affecting 1 in 3 adults The team, led by Ioannis Kamzolas and Thodoris Koutsandreas at @ebi.embl.org, established a new methodology to integrate multi-modal patient data

medrxiv.orgGenetic dose-response modelling predicts drug mechanisms, dosing, and adverse eventsUnderstanding how changes in gene function affect disease risk is central to drug development. Genetic variants are natural perturbations of gene activity and provide an opportunity to systematically ...

7 July

VIDRA is out now on medRxiv! Variant-Informed Dose-Response Analysis (VIDRA) is a computational framework which infers genetic dose-response relationships by integrating trait-associated variants across a spectrum of allele frequencies and functional consequences. www.medrxiv.org/content/10.6...

7 July

The team used over 1.6 million variants in the Open Targets Platform to generate over 148,000 dose-response-like gene-phenotype relationships. The genes were then ranked for their therapeutic potential, identifying many potential new targets.

“The scale at which we’re doing things, and in such an unbiased way, means that anything could come out of it. You have to be open to a new theory or something completely out of the ordinary happening.” Lewis Evans is @sangerinstitute.bsky.social Senior Staff Scientist and Open Targets project lead

He estimates his team has carried out over 100 whole genome CRISPR screens, and to date they estimate that they’ve grown at least 5 billion neurons. “But then, a human brain has about 80 billion cortical neurons, so we’re not quite there yet!”

blog.opentargets.orgSpotlight: Lewis EvansLewis Evans is an Open Targets project lead and Senior Staff Scientist at the Wellcome Sanger Institute. He studies the genetics of neurodegeneration. As part of his project NeuroFlux, Lewis interacts...

He studies the genetics of neurodegeneration, specifically autophagy and lysosomal pathways which are disease hallmarks His team uses the rare familial forms of Alzheimer's and Parkinson's as genetic anchors to look at the extremes of the disease Find out more: blog.opentargets.org/spotlight-le...

The Open Targets Platform 26.06 release is out now! ✋ 🔴 Find out about all the updates on the blog: blog.opentargets.org/open-targets...

23 June

“There isn’t anywhere else in the world where you’ve got genomics, computational, clinical, biological, and pharmaceutical expertise all in one group or consortium.” @mhaniffa.bsky.social discusses her experience working with partners across industry and academia as part of her Open Targets project

blog.opentargets.orgSpotlight: Muzlifah Haniffa"I’m a dermatologist, and my research straddles the disciplines of genomics, immunology, skin, and human development. I want to make a difference to human health, focusing on understanding how the hum...

23 June

Find out more: Find out more: blog.opentargets.org/spotlight-mu...

blog.opentargets.orgEnsuring stability of the Open Targets Platform: the case for automated end-to-end testingAs a platform grows in complexity, maintaining stability becomes increasingly difficult. The Open Targets Frontend Team has introduced automated end-to-end testing to ensure that core user journeys an...

18 June

How do you ensure the stability of a platform with millions of data points updated every release? You start testing patterns In the last release of the Open Targets Platform, we implemented automated end-to-end testing into our development workflow 🧬🖥️ blog.opentargets.org/end-to-end-t...

Open Targets reposted

Wellcome Sanger Institute

@sangerinstitute.bsky.social

15 June

New study into Crohn’s disease helps explain why gut inflammation persists, and could help unlock more targeted treatments for patients. Researchers analysed millions of gut cells, uncovering lasting molecular changes and key inflammatory immune cells. 👇 www.sanger.ac.uk/news_item/ce...

sanger.ac.ukCellular study maps gene activity changes across more than 50 gut cell types in Crohn’s diseaseThe latest IBDverse study identifies the genes expressed in Crohn's disease, revealing a lasting 'molecular scar' in the gut lining.

nature.comSingle-cell RNA sequencing of terminal ileal biopsies identifies signatures of Crohn’s disease pathogenesis - Nature GeneticsIBDverse is a single-cell RNA atlas of terminal ileal biopsies comprising 1.1 million cells from 111 patients with Crohn’s disease and 232 healthy participants. Analysis of the data identifies genes, ...

15 June

Out now in Nature Genetics! The largest single-cell RNA sequencing dataset of terminal ileal biopsies profiles 1.1 million cells from over 100 Crohn’s disease patients and over 200 healthy controls. Crohn’s disease is a type of inflammatory bowel disease (IBD) www.nature.com/articles/s41...

In particular, they found an upregulation of MHC-I driven by interferon, which persists in progenitor cells after visible inflammation heals. They also point to ITGA4+ macrophages as key drivers of inflammation, acting through JAK/STAT signalling and cytokine expression.

15 June

This work, part of a broader ‘IBDverse’ project in the Anderson lab, was a collaboration between Open Targets, the @sangerinstitute.bsky.social, and @cuh.nhs.uk Congratulations to the team!

The team led by @krzakmonika.bsky.social, @tobioinformatics.bsky.social, Leland Taylor, and @gastrogrj.bsky.social, uncover genes aberrantly expressed in Crohn’s disease, where expression is specific to given cell types/cellular responses, and that are most likely to have a causal role in disease

9 June

“Open Targets has had the single biggest impact in integrating the @sangerinstitute.bsky.social and @ebi.embl.org science, above and beyond any other initiative I’ve seen in that time." 🤝

blog.opentargets.orgHow Open Targets bridges academic science and pharmaceutical expertiseOpen Targets’ most successful collaborations are built on strong connections and regular communication between academic and industry partners at every stage of a project’s lifecycle. A decade after it...

9 June

Mathew Garnett was one of the first group leaders to receive an Open Targets project award. He discusses how Open Targets projects brings together academic and industry teams in a unique research partnership model. Find out more: blog.opentargets.org/how-open-tar...

nature.comCell-type-resolved genetic variation shapes inflammatory bowel disease risk - NatureSingle-cell mapping of cis-expression quantitative trait loci in inflammatory bowel disease revealed distal, enhancer-enriched variants detected at the cell-type level more frequently co-loc...

Out now in Nature! Genetic analysis of the largest single-cell dataset of Inflammatory Bowel Disease (IBD)-relevant tissues nominates effector genes and cell types at over half of known IBD loci, including 74 for which this is the first candidate effector gene 🖥️🧬 www.nature.com/articles/s41...

These findings help resolve the biology of IBD, and nominate targets for drug development or repurposing. A similar approach could be applied to other complex diseases to nominate effector genes from GWAS loci.

Congratulations to the team at the @sangerinstitute.bsky.social, Open Targets, and Cambridge University Hospitals NHS Foundation Trust!

To test this hypothesis, they generated the largest collection of single-cell RNA sequencing data from IBD-relevant sites (terminal ileum, rectum, blood), resulting in nearly 2.2 million single-cell transcriptomes from over 400 individuals including 125 with IBD.

By mapping eQTLs at three progressively higher resolutions, they found over 84,000 eQTLs in 251 cellular annotations. Notably, many eQTLs were only found at higher resolutions, and cell-type-level eQTLs were more than twice as likely to colocalise with IBD GWAS loci than tissue-level eQTLs.

Genetics are a good starting point for drug development, but while Genome Wide Association Studies have nominated loci for IBD, only a fraction of these have successfully been linked to causal genes with current eQTL discovery methods, which often rely on bulk RNA sequencing of heterogeneous tissues