Evidence mapPaperPMID 41299435Full record

ArticleBMC medicine2025

Immune cell-based transcriptomic Mendelian randomization and colocalization study on type 1 diabetes.

Julie Sklar, David Stacey, Grace Nickel, Adam S Butterworth, Elias Allara, Liam Gaziano

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Article in BMC medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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1 · What the graph read from it

What it found

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2 · The registry

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3 · Its place in the literature

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4 · The record

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5 · Who and what money

Authors and funding

6 authors.

Julie Sklar *Frank H. Netter MD School of Medicine, Quinnipiac University, North Haven, CT, USA.
David Stacey *Australian Centre for Precision Health, Unit of Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, Australia.
Grace NickelHarvard Medical School, Boston, MA, USA.
Adam S ButterworthBritish Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Elias Allara *British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Liam Gaziano *Harvard Medical School, Boston, MA, USA. lcg41@medschl.cam.ac.uk.

Funding

British Heart Foundation FKZ 81X2100281Health Data Research UK R2071CNRNIHR Cambridge Biomedical Research Centre NIHR203312
6 · The paper itself

Abstract

backgroundInterventions to prevent type 1 diabetes (T1D), an immune-mediated disease requiring lifelong treatment, remain limited. We sought to identify novel therapeutic targets for T1D through Mendelian randomization and colocalization using immune cell-derived instruments.

methodsWe selected locally acting genetic variants from 14 transcriptomic studies to instrument expression of 8998 genes measured in immune cell types. Outcome associations were obtained from a T1D genome-wide association study that included 18,942 cases and 501,638 controls. Follow-up analyses included assessments of horizontal pleiotropy and novelty, as well as phenome-wide scans with colocalization (PheWAS-coloc) of instrumental variants.

resultsWe prioritized 21 genes (CLNK, EED, LZTFL1, MGAT4A, NAA38, NFKB1, PHACTR4, PHLPP2, PLEKHA1, P2RY12, REST, RGS14, SERPINB6, SESN3, SLC25A29, SPAG1, STIM2, THEMIS, TMEM80, VSIR, ZNF217) that have not been identified in previous T1D genome-wide association studies. Notably, higher genetically predicted VSIR (encoding the immune checkpoint protein VISTA) was associated with decreased risk of T1D, providing human genetic support that complements existing animal-model evidence for VISTA's protective role in autoimmune diseases. We also prioritized P2RY12, which is targeted by several approved drugs, revealing a possible repurposing opportunity. PheWAS-coloc analyses further linked P2RY12 expression to Epstein-Barr virus EBNA-1 antibody levels, implicating a pathway relevant to autoimmunity.

conclusionsOur findings provide novel avenues for drug development and repurposing to prevent or delay T1D onset.

Indexed as

Diabetes Mellitus, Type 1Mendelian Randomization AnalysisTranscriptomeGenetic Predisposition to DiseaseGenome-Wide Association StudyHumansPolymorphism, Single NucleotideDrug developmentGenetic epidemiologyMendelian randomizationTranscriptomicsType 1 diabetes

Identifiers

PMID41299435
PMCPMC12751804

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.