Latest publication

BMC Med Genomics. 2025 Jun 2;18(1):101. doi: 10.1186/s12920-025-02171-y.

ABSTRACT

Loss-of-function variants in MDA5, a key sensor of double-stranded RNA from viruses and retroelements, have been associated with protection from type 1 diabetes (T1D) in genome-wide association studies (GWAS). MDA5 loss-of-function variants have also been reported to increase the risk of inflammatory bowel disease (IBD). Whether these associations are linked or extend to other diseases remains unclear. Here, fine-mapping analysis of four large GWAS datasets shows that T1D-protective loss-of-function MDA5 variants also protect against psoriasis and hypothyroidism, while increasing the risk of IBD. The degree of autoimmune protection and IBD risk were linearly proportional. The magnitudes of the odds ratios for autoimmune protection and IBD risk were larger for rare MDA5 variants than for common variants, which were differentially expressed in different geographic populations. Our analysis suggests MDA5 genetic variants offer a direct fitness trade-off between viral clearance and autoimmune tissue damage.

PMID:40457382 | DOI:10.1186/s12920-025-02171-y

Nat Commun. 2025 Jun 2;16(1):5122. doi: 10.1038/s41467-025-60056-1.

ABSTRACT

Polygenic scores, which estimate an individual's genetic propensity for a disease or trait, have the potential to become part of genomic healthcare. Neural-network based deep-learning has emerged as a method of intense interest to model complex, nonlinear phenomena, which may be adapted to exploit gene-gene and gene-environment interactions to potentially improve polygenic scores. We fit neural-network models to both simulated and 28 real traits in the UK Biobank. To infer the amount of nonlinearity present in a phenotype, we also present a framework using neural-networks, which controls for the potential confounding effect of linkage disequilibrium. Although we found evidence for small amounts of nonlinear effects, neural-network models were outperformed by linear regression models for both genetic-only and genetic+environmental input scenarios. In this work, we find that the usefulness of neural-networks for generating polygenic scores may currently be limited and confounded by joint tagging effects due to linkage disequilibrium.

PMID:40456720 | DOI:10.1038/s41467-025-60056-1

EClinicalMedicine. 2025 May 2;83:103194. doi: 10.1016/j.eclinm.2025.103194. eCollection 2025 May.

ABSTRACT

BACKGROUND: SARS-CoV-2 is known to impact patients with cancer adversely. Previous meta-analyses have lacked clarity on the recency of cancer diagnosis, anti-cancer treatment durations, and SARS-CoV-2 specific variants of concern (VOC). This study aimed to compare SARS-CoV-2 multivariable-adjusted clinical outcomes between patients with cancer and those without cancer, identifying key risk factors spanning pre- and post-Omicron periods.

METHODS: In this systematic review and meta-analysis, we identified from Medline, Embase, Cochrane Central, and the WHO COVID-19 Research Database prospective and retrospective case-control studies and cohort studies published from 1st January 2019 to 22nd November 2024. We included case-control and cohort studies comparing at least 10 patients with active cancer (diagnosed or treated within three years prior to SARS-CoV-2 infection) to controls without cancer using multivariable analyses. Exclusion criteria included lack of clarity about active/inactive status of cancer, lack of a control group without cancer, lack of multivariate analysis comparing outcomes of interest in patients with active cancer vs patients without cancer, case reports or case series, and SARS-CoV-2 diagnosis not confirmed via laboratory testing. Outcomes measured were SARS-CoV-2 infection severity (WHO ordinal scale) and mortality differences by tumour type, treatment, and VOC (using sequencing data from NCBI Genbank and GISAID). A random-effects meta-analysis model was applied. The systematic review was PRISMA compliant and was registered with PROSPERO, CRD420234454524.

FINDINGS: Of 35,501 studies initially identified, 30 met eligibility criteria and were included in the meta-analysis, comprising 281,270 patients with cancer and 18,876,411 controls. Using the Agency for Healthcare Research and Quality (AHRQ) risk of bias standards, 21 studies were rated good, one study rated was fair, and eight studies were rated poor. We found higher mortality odds ratios (OR) in patients with cancer infected with SARS-CoV-2: 1·40 (95% CI: 1·12-1·73, I2 = 98·1%) for solid tumours and 2·10 (95% CI: 1·43-3·07, I2 = 97·3%) for haematological malignancies, with the difference in mortality between these groups not reaching statistical significance (Q (1) = 3·32; p = 0·0068). Amongst the solid cancers, thoracic and colorectal were linked to increased odds of mortality (ORs: 2·63 [95% CI: 1·65-4·20, I2 = 98·7%], and 1·65 [95% CI: 1·26-2·15, I2 = 92·7%], respectively). Metastatic cancers (OR: 3·59; 95% CI: 1·07-12·04, I2 = 99·5%) were also linked to greater odds of mortality compared to localised cancers (OR: 1·76; 95% CI: 1·32-2·34, I2 = 96·6%; p = 0·26). No cancer types showed a reduced risk vs controls. Mortality varied significantly among VOCs; Alpha (OR: 4·59; 95% CI: 2·66-7·92, I2: N/A) and Omicron (OR: 2·74; 95% CI: 1·84-4·09, I2 = 90·2%) were more associated with death than the ancestral Wu-1 (OR: 1·43; 95% CI: 1·14-1·80, I2 = 98·2%) and Delta (OR: 1·94; 95% CI: 1·65-2·29, I2:N/A) variants (X2 (4) = 20·4; p = 0·0004).

INTERPRETATION: This comprehensive meta-analysis indicates that patients with active cancer with SARS-CoV-2 have a higher risk of mortality and hospitalisation than those without cancer. The risk of death was comparable between active solid and haematological tumours. SARS-CoV-2 severity and mortality risks were higher with thoracic, colorectal, or any metastatic cancers. Additionally, differences were noted in mortality risks across VOCs, diverging from VOC-associated mortality patterns in the general population. However, the strict three-year cutoff used to define active cancer excludes studies that used broader cancer criteria (i.e., any history of cancer), which may limit generalisability. Further limitations include varied definitions of disease severity, retrospective data collection, incomplete vaccination or lineage data, and significant between-study heterogeneity, potentially influencing these findings.

FUNDING: Cancer Research UK; UK Research and Innovation.

PMID:40453535 | PMC:PMC12123352 | DOI:10.1016/j.eclinm.2025.103194

Cell Rep. 2025 May 30;44(6):115754. doi: 10.1016/j.celrep.2025.115754. Online ahead of print.

ABSTRACT

MDA5 recognizes double-stranded RNA (dsRNA) from viruses and retroelements. Cooperative filament formation and ATP-dependent proofreading confer MDA5 with the necessary sensitivity and specificity for dsRNA. Many MDA5 genetic variants are associated with protection from autoimmune disease while increasing the risk of infection and chronic inflammation. How these variants affect RNA sensing remains unclear. Here, we determine the consequences of autoimmune-protective variants on the molecular structure and activities of MDA5. Rare variants E627∗ and I923V reduce the interferon response to picornavirus infection. E627∗ does not bind RNA. I923V is ATPase hyperactive, causing premature dissociation from dsRNA. Cryoelectron microscopy (cryo-EM) structures of MDA5 I923V bound to dsRNA at different stages of ATP hydrolysis reveal smaller RNA binding interfaces, leading to excessive proofreading activity. Variants R843H and T946A, which are genetically linked and cause mild phenotypes, did not affect cytokine induction, suggesting an indirect disease mechanism. In conclusion, autoimmune-protective MDA5 variants dampen MDA5-dependent signaling via multiple mechanisms.

PMID:40450684 | DOI:10.1016/j.celrep.2025.115754

PLoS Genet. 2025 May 27;21(5):e1011697. doi: 10.1371/journal.pgen.1011697. Online ahead of print.

ABSTRACT

Linking GWAS variants to their causal gene and context remains an ongoing challenge. A widely used method for performing this analysis is the coloc package for statistical colocalisation analysis, which can be used to link GWAS and eQTL associations. Currently, coloc assumes that all variants in a region are equally likely to be causal, despite the success of fine-mapping methods that use additional information to adjust their prior probabilities. In this paper we propose and implement an approach for specifying variant-specific prior probabilities in the coloc method. We describe and compare six source of information for specifying prior probabilities: non-coding constraint, enhancer-gene link scores, the output of the PolyFun method and three estimates of eQTL-TSS distance densities. Using simulations and analysis of ground-truth pQTL-eQTL colocalisations we show that variant-specific priors, particularly the eQTL-TSS distance density priors, can improve colocalisation performance. Furthermore, across GWAS-eQTL colocalisations variant-specific priors changed colocalisation significance in up to 14.1% of colocalisations, at some loci revealing the likely causal gene.

PMID:40424384 | DOI:10.1371/journal.pgen.1011697

PLoS Pathog. 2025 Apr 28;21(4):e1013109. doi: 10.1371/journal.ppat.1013109. eCollection 2025 Apr.

ABSTRACT

An important feature of the evolution of the SARS-CoV-2 virus has been the emergence of highly mutated novel variants, which are characterised by the gain of multiple mutations relative to viruses circulating in the general global population. Cases of chronic viral infection have been suggested as an explanation for this phenomenon, whereby an extended period of infection, with an increased rate of evolution, creates viruses with substantial genetic novelty. However, measuring a rate of evolution during chronic infection is made more difficult by the potential existence of compartmentalisation in the viral population, whereby the viruses in a host form distinct subpopulations. We here describe and apply a novel statistical method to study within-host virus evolution, identifying the minimum number of subpopulations required to explain sequence data observed from cases of chronic infection, and inferring rates for within-host viral evolution. Across nine cases of chronic SARS-CoV-2 infection in hospitalised patients we find that non-trivial population structure is relatively common, with five cases showing evidence of more than one viral population evolving independently within the host. The detection of non-trivial population structure was more common in severely immunocompromised individuals (p = 0.04, Fisher's Exact Test). We find cases of within-host evolution proceeding significantly faster, and significantly slower, than that of the global SARS-CoV-2 population, and of cases in which viral subpopulations in the same host have statistically distinguishable rates of evolution. Non-trivial population structure was associated with high rates of within-host evolution that were systematically underestimated by a more standard inference method.

PMID:40294077 | PMC:PMC12061394 | DOI:10.1371/journal.ppat.1013109

Nat Commun. 2025 Apr 17;16(1):3689. doi: 10.1038/s41467-025-58977-y.

ABSTRACT

B cells have important functions in gut homeostasis, and dysregulated B cell populations are frequently observed in patients with inflammatory bowel diseases, including both ulcerative colitis (UC) and Crohn's disease (CD). How these B cell perturbations contribute to disease remains largely unknown. Here, we perform deep sequencing of the B cell receptor (BCR) repertoire in four cohorts of patients with CD, together with healthy controls and patients with UC. We identify BCR clones that are shared between patients with CD but not found in healthy individuals nor in patients with UC, indicating CD-associated B cell immune responses. Shared clones are present in the inflamed gut mucosa, draining intestinal lymph nodes and blood, suggesting the presence of common CD-associated antigens that drive B cell responses in CD patients.

PMID:40246842 | PMC:PMC12006383 | DOI:10.1038/s41467-025-58977-y

Nature. 2025 Apr 16. doi: 10.1038/s41586-025-08980-6. Online ahead of print.

ABSTRACT

Somatic DNMT3A R882 codon mutations drive the most common form of clonal haematopoiesis (CH) and are associated with increased acute myeloid leukaemia (AML) risk1,2. Preventing expansion of DNMT3A-R882-mutant haematopoietic stem/progenitor cells (HSPCs) may therefore avert progression to AML. To identify DNMT3A-R882-mutant-specific vulnerabilities, we conducted a genome-wide CRISPR screen on primary mouse Dnmt3aR882H/+ HSPCs. Amongst the 640 vulnerability genes identified, many were involved in mitochondrial metabolism and metabolic flux analysis confirmed enhanced oxidative phosphorylation usage in Dnmt3aR882H/+ vs Dnmt3a+/+ (WT) HSPCs. We selected citrate/malate transporter Slc25a1 and complex I component Ndufb11, for which pharmacological inhibitors are available, for downstream studies. In vivo administration of SLC25A1 inhibitor CTPI2 and complex I inhibitors IACS-010759 and metformin, suppressed post-transplantation clonal expansion of Dnmt3aR882H/+, but not WT, LT-HSC. The effect of metformin was recapitulated using a primary human DNMT3A-R882 CH sample. Notably, analysis of 412,234 UK Biobank (UKB) participants revealed that individuals taking metformin had markedly lower prevalence of DNMT3A-R882-mutant CH, after controlling for potential confounders including glycated haemoglobin, diabetes and body mass index. Collectively, our data propose modulation of mitochondrial metabolism as a therapeutic strategy for prevention of DNMT3A-R882-mutant AML.

PMID:40239706 | DOI:10.1038/s41586-025-08980-6

bioRxiv [Preprint]. 2025 Mar 19:2025.03.19.643996. doi: 10.1101/2025.03.19.643996.

ABSTRACT

Chronic inflammation in autoimmunity is driven by T cell hyperactivation. This unregulated response to self is fuelled by heightened metabolic programmes, which offers a promising new direction to uncover novel treatment strategies. α/β-hydrolase domain-containing protein 11 (ABHD11) is a mitochondrial hydrolase that maintains the catalytic function of α-ketoglutarate dehydrogenase (α-KGDH), and its expression in CD4+ T cells has been linked to remission status in rheumatoid arthritis (RA). However, the importance of ABHD11 in regulating T cell metabolism and function - and thus, the downstream implication for autoimmunity - is yet to be explored. Here, we show that pharmacological inhibition of ABHD11 dampens cytokine production by human and mouse T cells. Mechanistically, the anti-inflammatory effects of ABHD11 inhibition are attributed to increased 24,25-epoxycholesterol (24,25-EC) biosynthesis and subsequent liver X receptor (LXR) activation, which arise from a compromised TCA cycle. The impaired cytokine profile established by ABHD11 inhibition is extended to two patient cohorts of autoimmunity. Importantly, using a murine model of accelerated type 1 diabetes (T1D), we show that targeting ABHD11 suppresses cytokine production in antigen-specific T cells and delays the onset of diabetes in vivo. Collectively, our work provides pre-clinical evidence that ABHD11 is an encouraging drug target in T cell-mediated autoimmunity.

PMID:40166327 | PMC:PMC11957007 | DOI:10.1101/2025.03.19.643996

Commun Biol. 2025 Mar 22;8(1):478. doi: 10.1038/s42003-025-07848-9.

ABSTRACT

GPR35 is an orphan G-protein coupled receptor that has been implicated in the development of cancer. GPR35 regulates the Na+/K+-ATPase's pump and signalling function. Here we show GPR35's critical role in ion flux that in turn controls cellular osmotic pressure and Na+-dependent transport in HepG2 and SW480 cells. GPR35 deficiency results in increased levels of intracellular Na+, osmotic stress and changes in osmolytes leading to increased cells size and decreased glutamine import in vitro and in vivo. The GPR35-T108M risk variant, which increases risk for primary sclerosing cholangitis and inflammatory bowel disease, leads to lower intracellular Na+ levels, and enhanced glutamine uptake. High salt diet (HSD) in wildtype mice resembles the intestinal epithelial phenotype of their Gpr35-/- littermates with decreased Goblet cell size and numbers. This indicates that GPR35's regulation of the Na+/K+-ATPase controls ion homeostasis, osmosis and Na+-dependent transporters.

PMID:40121360 | PMC:PMC11929815 | DOI:10.1038/s42003-025-07848-9