Lightnews — Scholar-powered news

Reposted by Mike Weedon

Nature Metabolism @natmetabolism.nature.com · 1d

RESEARCH | J Murray Leech, KA Patel et al.
@exeter.ac.uk

Polygenic risk for T2D modifies the onset and phenotypic variability of maturity-onset diabetes of the young (MODY) 🧪

Common genetic variants modify disease risk and clinical presentation in monogenic diabetes - Nature Metabolism

In clinical and population-based cohorts, a strong contribution of polygenic risk for type 2 diabetes (T2D) significantly modifies the onset and phenotypic variability of maturity-onset diabetes of the young (MODY). This polygenic T2D burden may also account for MODY-like individuals without identified monogenic causes.

bit.ly

3 8

Reposted by Mike Weedon

James Russ-Silsby @jamesr-s.bsky.social · Sep 15

I’m excited to share the 2 newest Neonatal diabetes genes: RNU4ATAC and RNU6ATAC. These genes encode snRNA components of the minor spliceosome and biallelic variants in them cause monogenic autoimmune diabetes. If you are at #EASD, come to Matt Johnson’s talk Tuesday @4pm in Milan hall to hear more.

The minor spliceosome is a master immune regulator

Pathogenic variants in non-coding genes are emerging as critical contributors to human rare diseases. We identified 19 individuals with early-onset diabetes (diagnosed <5 years) and additional clinica...

www.medrxiv.org

7 5

Reposted by Mike Weedon

Nature Metabolism @natmetabolism.nature.com · Sep 9

Common genetic variants modify disease risk and clinical presentation in monogenic diabetes

Nature Metabolism, Published online: 09 September 2025; doi:10.1038/s42255-025-01372-0In clinical and population-based cohorts, a strong contribution of polygenic risk for type 2 diabetes (T2D) significantly modifies the onset and phenotypic variability of maturity-onset diabetes of the young (MODY). This polygenic T2D burden may also account for MODY-like individuals without identified monogenic causes.

bit.ly

2 3

Reposted by Mike Weedon

Jacques Murray Leech @jacquesml.bsky.social · Sep 9

Now out in @natmetabolism.nature.com! Excited to share our work showing how common genetic changes shape how diabetes presents in MODY (Maturity-Onset Diabetes of the Young). Our findings highlight the growing overlap between monogenic and polygenic forms of diabetes.

www.nature.com/articles/s42...

Common genetic variants modify disease risk and clinical presentation in monogenic diabetes - Nature Metabolism

In clinical and population-based cohorts, a strong contribution of polygenic risk for type 2 diabetes (T2D) significantly modifies the onset and phenotypic variability of maturity-onset diabetes of th...

www.nature.com

1 3 5

Reposted by Mike Weedon

Aparajita Sriram @aparajita-sriram.bsky.social · Aug 27

Our paper is now out on Diabetes!
diabetesjournals.org/diabetes/art...

Rare Variants in NEUROD1 and PDX1 Are Low-Penetrance Causes of MODY, Whereas Those in APPL1 and WFS1 Are Not Associated With MODY

An accurate genetic diagnosis of maturity-onset diabetes of the young (MODY) is critical for personalized treatment. To avoid misdiagnosis, only genes with

diabetesjournals.org

4 3

Reposted by Mike Weedon

Jacques Murray Leech @jacquesml.bsky.social · Aug 11

New preprint out now! We show polygenic background shapes GCK-MODY clinical presentation. In >1,000 cases, higher polygenic risk increased the chance of exceeding diagnostic diabetes thresholds, highlighting how monogenic & polygenic factors jointly shape disease. #Genetics

medRxivpreprint @medrxivpreprint.bsky.social · Aug 9

Polygenic Background Contributes to GCK-MODY Clinical Presentation and Glycaemic Variability https://www.medrxiv.org/content/10.1101/2025.08.04.25332935v1

1 6 8

Reposted by Mike Weedon

Robin Hofmeister @rjhfmstr.bsky.social · Aug 6

🚨 Our parent-of-origin study is out in Nature! 🧬
Maternal and paternal alleles can have distinct — even opposite — effects on human traits, revealing a hidden layer of genetic architecture that standard GWAS miss.
🔗 www.nature.com/articles/s41...

Highlights below!

2 55 120

Reposted by Mike Weedon

erinltempleman.bsky.social @erinltempleman.bsky.social · Jul 23

🚨Big news! Excited to share my first PhD paper!🎉
We validated & improved a T1D risk model using TrialNet data (originally from TEDDY), boosting accuracy 📈
bmcmedicine.biomedcentral.com/articles/10....
Try the web tool 👉 t1dpredictor.diabetesgenes.org
#T1D #RiskPrediction #PrecisionMedicine #TrialNet

Development and recalibration of a multivariable type 1 diabetes prediction model for type 1 diabetes across multiple screening studies - BMC Medicine

Background Accurate type 1 diabetes prediction is important to facilitate screening for pre-clinical type 1 diabetes to enable potential early disease-modifying interventions and to reduce the risk of...

bmcmedicine.biomedcentral.com

5 11

Reposted by Mike Weedon

The Lancet Diabetes & Endocrinology @thelancetendo.bsky.social · Jul 22

New Research:
Non-autoimmune, insulin-deficient #diabetes in children and young adults in #Africa: evidence from the Young-Onset Diabetes in sub-Saharan Africa (YODA) cross-sectional study thelancet.com/journals/lan... #T1D
#OpenAccess

#MedSky #EndoSky

Non-autoimmune, insulin-deficient diabetes in children and young adults in Africa: evidence from the Young-Onset Diabetes in sub-Saharan Africa (YODA) cross-sectional study

In sub-Saharan Africa, clinically diagnosed type 1 diabetes is heterogeneous, comprising classic autoimmune type 1 diabetes and a novel, non-autoimmune, insulin-deficient diabetes subtype. There is ev...

thelancet.com

1 4 5

Reposted by Mike Weedon

James Russ-Silsby @jamesr-s.bsky.social · Jul 3

Really proud of this Exeter–Stanford collaboration identifying bi-allelic variants in PAX4 as a novel cause of transient neonatal diabetes—the first new genetic cause of this subtype described in over a decade. This work expands our understanding of beta cell development.
🔗 doi.org/10.1016/j.mo...

Complete Loss of PAX4 causes Transient Neonatal Diabetes in Humans

Gene discovery studies in individuals with diabetes diagnosed within 6 months of life (neonatal diabetes, NDM) can provide unique insights into the de…

www.sciencedirect.com

1 7 12

Reposted by Mike Weedon

medRxivpreprint @medrxivpreprint.bsky.social · Jul 1

Population prevalence, penetrance, and mortality for genetically confirmed MODY https://www.medrxiv.org/content/10.1101/2025.06.30.25330354v1

4 3

Reposted by Mike Weedon

Zoltán Kutalik @zkutalik.bsky.social · Jun 27

Lausanne Comp Bio Symposium 2025 (cbiosymposium.unil.ch)

🗓 Abstract deadline 30 June (𝟑 𝐝𝐚𝐲𝐬 𝐭𝐨 𝐠𝐨!!!)
🎤 Oral presentation notifications: 7 July
✅ Early Bird registration deadline: 11 July
💰 Registration fee for non-PI: 150 CHF

8 8

Reposted by Mike Weedon

Luke Sharp @luke-sharp.bsky.social · Jun 19

MODY is prevalent in later onset diabetes. Really proud to announce the release of a preprint of our paper assessing MODY in people diagnosed with diabetes later in life!!
#MonogenicDiabetes

medRxivpreprint @medrxivpreprint.bsky.social · Jun 19

MODY is prevalent in later-onset diabetes, has potential for targeted therapy but is challenging to identify https://www.medrxiv.org/content/10.1101/2025.06.17.25329143v1

6 5

Reposted by Mike Weedon

Anna Gloyn @annagloyn.bsky.social · Jun 4

Out today from #HectorOrtega & #SethASharp A state of the art review on polygenic risk scores (#PRS) in diabetes. This is your #101 on what we currently know about them and their application to understanding disease heterogeneity & clinical translation.

Read for free here - rdcu.be/eprel

6 9

Reposted by Mike Weedon

Aparajita Sriram @aparajita-sriram.bsky.social · Jun 4

Excited to share the preprint of our paper (my first paper!) looking at limited evidence MODY genes. We use rare variant burden testing and one of the largest MODY cohorts to evaluate the pathogenicity of these genes. This evidence can help inform clinical guidelines in MODY genetic testing!

medRxivpreprint @medrxivpreprint.bsky.social · May 8

NEUROD1 and PDX1 are low penetrance causes of MODY while rare variants in APPL1 and WFS1 are not associated with MODY https://www.medrxiv.org/content/10.1101/2025.05.07.25327066v1

4 3

Reposted by Mike Weedon

James Fasham @jamesfasham.bsky.social · May 22

Congratulations @carolinefwright.bsky.social for being elected to a fellow of the Academy of Medical Sciences! 🍾!

news.exeter.ac.uk/faculty-of-h...

@nihrexeterbrc.bsky.social

1 3 10

Reposted by Mike Weedon

Caroline Wright @carolinefwright.bsky.social · May 1

⬇️ again. I feel the need to re-post this point pretty much every week! Benign variants are not low penetrance.

Nicky Whiffin @nickywhiffin.bsky.social · Mar 3

Key points:
1. Observation in a single case != pathogenic
2. Pre-selected cohorts warrant special care (controls are important!)
3. To make claims about reduced penetrance (as they do in the discussion) we first need evidence of pathogenicity (which there isn’t here)

6/7

1 4

Reposted by Mike Weedon

Amber Luckett @ambermluckett.bsky.social · Apr 25

Our new paper updating GRS2 with a new tool to easily generate standardised T1DGRS 🧬 Thanks to Seth Sharp, @annagloyn.bsky.social, Richard Oram and @mnweedon.bsky.social for a great collaboration! tinyurl.com/4bsaz9hx

Standardized Measurement of Type 1 Diabetes Polygenic Risk Across Multiancestry Population Cohorts

Amber M. Luckett, Richard A. Oram, Aaron J. Deutsch, Hector I. Ortega, Diane P. Fraser, Kaavya Ashok, Alisa K. Manning, Josep M. Mercader, Manuel A. Rivas,

tinyurl.com

2 2

Reposted by Mike Weedon

Caroline Wright @carolinefwright.bsky.social · Apr 10

"Remember that it's not only scientists that read your papers" - sage advice from author of a beautiful poem 'Proband', which began life as a response to our DDD NEJM paper, linking genomic science and its patients. www.consilience-journal.com/issue-17-pro...

Proband — Consilience

www.consilience-journal.com

2 6 13

Reposted by Mike Weedon

James Russ-Silsby @jamesr-s.bsky.social · Apr 4

There are fewer than 10 documented genetic causes of Transient Neonatal Diabetes (TNDM) and now PAX4 is one of them! Really proud of this collaborative work done between the Neonatal Diabetes Research Team at Exeter and the Translational Genomics of Diabetes Lab in Stanford.

medRxivpreprint @medrxivpreprint.bsky.social · Apr 3

Complete Loss of PAX4 causes Transient Neonatal Diabetes in Humans https://www.medrxiv.org/content/10.1101/2025.04.01.25324926v1

8 10

Reposted by Mike Weedon

Caroline Wright @carolinefwright.bsky.social · Apr 3

Come and work with us - 2 Graduate Research Assistant positions available in genomic medicine, with a particular focus on variant interpretation and data analysis. Part of the Wellcome-funded PARADIGM project, and based in beautiful Exeter UK! jobs.exeter.ac.uk/hrpr_webrecr...

5 9

Reposted by Mike Weedon

Jeff Spence @jeffspence.github.io · Mar 28

A really nice paper by @drghawkes.bsky.social et al. argues that rare and common genetic associations converge on the same genes.

While this seems at odds with our recent work about how burden tests and GWAS prioritize different genes, our results agree (🧬🧪🧵 1/6)

www.biorxiv.org/content/10.1...

Whole-genome sequencing analysis of anthropometric traits in 672,976 individuals reveals convergence between rare and common genetic associations

Genetic association studies have mostly focussed on common variants from genotyping arrays or rare protein-coding variants from exome sequencing. Here, we used whole-genome sequence (WGS) data in 672,...

www.biorxiv.org

6 22 59

Reposted by Mike Weedon

Dr Gareth Hawkes @drghawkes.bsky.social · Mar 24

Excited to be able to announce I’ll be starting a 5-year MRC Career Development Award fellowship next week on the 1st April at the University of Exeter! Lots of work to do on whole genomes, and I’m hoping to keep contributing my small piece!

3 1 16

Reposted by Mike Weedon

Daniel MacArthur @dgmacarthur.bsky.social · Mar 15

New preprint! We worked with @msftresearch.bsky.social and @broadinstitute.org to see whether large language models (LLMs) can be useful to variant scientists in deciding whether genetic variants seen in a patient are responsible for their disease. tl;dr yes they can: www.biorxiv.org/content/10.1...

Evidence Aggregator: AI reasoning applied to rare disease diagnostics

Retrieving, reviewing, and synthesizing technical information can be time-consuming and challenging, particularly when requiring specialized expertise, as is the case of variant assessment for rare di...

www.biorxiv.org

1 47 140

Reposted by Mike Weedon

Caroline Wright @carolinefwright.bsky.social · Feb 27

Exciting times for genomics research @exeter.ac.uk @nihrexeterbrc.bsky.social! 🧬 New preprint from the team: using large-scale WGS from @ukbiobank.bsky.social and All of Us shows convergence between rare and common genetic associations, with implications for genetic architecture of complex traits.

Dr Gareth Hawkes @drghawkes.bsky.social · Feb 26

Really excited to share our next population-scale WGS work preprint. Here, we analyse three anthropometric traits in nearly 700,000 individuals (discovery UKB ~450K, replication AoU). We show, for these traits, that common and rare variant heritability is convergent

www.biorxiv.org/content/10.1...

Whole-genome sequencing analysis of anthropometric traits in 672,976 individuals reveals convergence between rare and common genetic associations

Genetic association studies have mostly focussed on common variants from genotyping arrays or rare protein-coding variants from exome sequencing. Here, we used whole-genome sequence (WGS) data in 672,...

www.biorxiv.org

4 5