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PubMed2026

Genetic evidence prioritizes circulating proteins for heart failure beyond shared BMI-related genetic liability.

BACKGROUND: Heart failure (HF) and body mass index (BMI) share substantial genetic architecture, which may lead genetically informed target discovery to preferentially identify adiposity-related pathways. We sought to identify circulating proteins associated with HF beyond this shared genetic component. METHODS: We applied GWAS-by-subtraction to overall HF, nonischemic HF, and nonischemic HF with reduced or preserved ejection fraction to derive BMI-related and BMI-subtracted HF components. We then performed proteome-wide cis-pQTL Mendelian randomization and colocalization using four independent proteomic cohorts, followed by tissue-specific eQTL colocalization, cardiac transcriptomic annotation, and druggability assessment. RESULTS: Compared with the original HF phenotypes, the BMI-subtracted components showed attenuated genetic correlations with BMI (0.045-0.147) while retaining 28 independent loci for overall HF and nine for nonischemic HF. Across 19,930 protein-HF tests, 11 associations involving nine proteins were prioritized by the Mendelian randomization and colocalization analyses. For example, a 1-SD increase in genetically predicted CELSR2 abundance was associated with lower overall HF risk (odds ratio, 0.96 [95% CI, 0.94-0.98]; P=8.6×10-7), whereas a 1-SD increase in genetically predicted CSF3 abundance was associated with higher nonischemic HF risk (odds ratio, 1.32 [95% CI, 1.18-1.48]; P=2.0×10-6). CELSR2 and TMEM106B colocalized with cis-eQTLs in failing left ventricular myocardium, and DAG1 showed cardiomyocyte enrichment with concordant downregulation in failing hearts. CONCLUSIONS: We identified nine circulating proteins associated with HF beyond the genetic component shared with BMI. These findings extend the range of genetically supported pathways implicated in HF and nominate candidate proteins for further mechanistic and therapeutic investigation.

Genetics↗

PubMed1975

[Effect of ACTH on extravascular protein circulation in the lymph and blood of rams].

Explore the source record for details and available documents.

Adrenocorticotropic Hormone↗

PubMed2025

Circulating inflammatory proteins as causal drivers and therapeutic targets in asthma: insights from genetic and pathway-based analyses.

OBJECTIVE: To identify circulating inflammatory proteins with potential causal roles in asthma development through integrated genetic and pathway-based analyses, and to evaluate their potential as therapeutic targets. METHODS: We used genetically anchored instrumental variables from 180 protein quantitative trait loci (pQTLs) to assess the causal effects of 91 circulating inflammatory proteins on asthma risk, using large-scale GWAS datasets. Analytical robustness was evaluated through pleiotropy and heterogeneity testing. Functional enrichment and literature-based pathway analyses were performed to support biological plausibility and validate findings. RESULTS: Four proteins showed significant causal effects on asthma: CCL19 and LIFR were protective (OR = 0.89 and 0.91, p ≤ 6.8E-03), while ARTN and IL6 were associated with increased risk (OR = 1.15 and 1.18, p ≤ 1.1E-04). We also identified reverse causal effects of asthma on 11 cytokines, including MMP10, TGFB1, IL33, and IL18R1. Most of these proteins were enriched in pathways related to cytokine signaling and immune response (p < 0.001). All identified proteins had prior literature support linking them to asthma or airway inflammation. CONCLUSIONS: Our findings highlight a subset of circulating inflammatory proteins that are likely causal in asthma pathogenesis and may serve as promising targets for therapeutic intervention. These results offer novel insights into the immunological mechanisms underlying asthma and support the utility of genetic causal inference in target prioritization.

Asthma↗

PubMed2025

Causal association between 91 circulating inflammatory proteins and primary open-angle glaucoma: a bidirectional Mendelian randomization study.

BACKGROUND: Glaucoma, especially primary open-angle glaucoma (POAG), is a leading cause of irreversible vision loss. While elevated intraocular pressure is a major risk factor, the pathogenesis of POAG also involves genetics, oxidative stress, abnormal hemodynamics, and inflammatory factors. The role of systemic inflammation in POAG remains a subject of debate. This study aimed to investigate the causal relationships between circulating inflammatory proteins and POAG using a bidirectional Mendelian randomization (MR) approach. METHODS: A bidirectional two-sample MR analysis was conducted using genome-wide association study summary statistics. The primary stage involved 91 circulating inflammatory proteins and POAG, followed by a replication stage to verify significant findings using independent data and meta-analysis. The random-effects inverse-variance weighted model was employed as the primary method, complemented by multiple sensitivity analyses employed to ensure robustness, including multivariable MR to adjust for potential confounders. RESULTS: In the primary stage, 9 circulating inflammatory proteins were found to have significant causal effects on POAG. Specifically, the higher levels of Delta and Notch-like epidermal growth factor-related receptor (DNER) (OR: 1.12, 95 % CI: 1.04-1.21, P = 0.004), leukemia inhibitory factor (LIF) (OR: 1.20, 95 % CI: 1.06-1.36, P = 0.003), matrix metalloproteinase-10 (MMP-10) (OR: 1.08, 95 % CI: 1.02-1.16, P = 0.013), and stem cell factor (SCF) (OR: 1.09, 95 % CI: 1.03-1.15, P = 0.005) were positively associated with the risk of POAG. Conversely, the levels of fibroblast growth factor 19 (FGF-19) (OR: 0.88, 95 % CI: 0.82-0.95, P = 0.002), interleukin-18 (IL-18) (OR: 0.92, 95 % CI: 0.86-0.99, P = 0.019), IL-18 receptor 1 (IL-18R1) (OR: 0.96, 95 % CI: 0.92-1.00, P = 0.037), tumor necrosis factor ligand superfamily member 14 (TNFSF14) (OR: 0.91, 95 % CI: 0.86-0.97, P = 0.004), and tumor necrosis factor-related activation-induced cytokine (TRANCE) (OR: 0.94, 95 % CI: 0.88-1.00, P = 0.041) exhibited inverse associations with the risk of POAG. Multivariable MR analysis adjusting for confounders supported the roles of DNER, FGF-19, IL-18, IL18R1, LIF, and SCF. The replication stage confirmed the significant associations for FGF-19 (OR: 0.89, 95 % CI: 0.84-0.95, P = 4.63 × 10-4), IL-18 (OR: 0.93, 95 % CI: 0.89-0.97, P = 0.002), IL-18R1 (OR: 0.96, 95 % CI: 0.93-0.99, P = 0.023), and LIF (OR: 1.18, 95 % CI: 1.04-1.34, P = 0.013). Sensitivity analyses further supported the robustness of these findings. CONCLUSION: This study elucidated the causal relationships between circulating inflammatory proteins and POAG, highlighting FGF-19, IL-18, IL-18R1, and LIF as potential therapeutic targets. These findings provide new insights for the prevention and management of POAG, although further studies are needed to understand the precise biological mechanisms.

Humans↗

PubMed2025

Circulating inflammatory proteins and osteomyelitis: A bidirectional Mendelian randomization and colocalization analysis.

Circulating inflammatory proteins (CIPs) have been implicated in the progression of osteomyelitis (OM); however, whether these proteins play a causal role or are merely a consequence remains unclear. This study aimed to assess the causal relationships between CIPs and OM using a bidirectional 2-sample Mendelian randomization (MR) approach. MR analyses were performed using genome-wide association study summary statistics for 91 inflammation-related proteins (n = 14,824) and OM (1881 cases and 3,91,037 controls). The inverse variance weighted method was used as the primary analytical approach, supplemented by MR-Egger, weighted median, simple mode, and weighted mode methods. Sensitivity analyses were conducted to evaluate heterogeneity, horizontal pleiotropy, and robustness. Colocalization analysis was applied to identify shared causal variants, and pathway enrichment analysis was used to explore underlying biological mechanisms. Forward MR analysis revealed that elevated levels of tumor necrosis factor-beta (TNF-β) were significantly associated with increased OM risk (odds ratio [OR] = 1.132; 95% confidence interval [CI]: 1.052-1.217; false discovery rate [FDR] = 0.027). Conversely, decreased levels of osteoprotegerin (OR = 0.772; 95% CI: 0.671-0.889; FDR = 0.015) and adenosine deaminase (OR = 0.811; 95% CI: 0.736-0.894; FDR < 0.001) were associated with increased OM risk. Reverse MR analysis identified increased levels of interleukin-15 receptor alpha, C-X-C motif chemokine ligand 1, fms-related tyrosine kinase 3 ligand, interleukin-20, interleukin-10 (IL10), C-C motif chemokine ligand 19, and CXCL6 as being significantly associated with OM susceptibility (all FDR < 0.05). Colocalization analysis provided strong evidence for a shared causal variant between TNF-β and OM (posterior probability for hypothesis 4 = 0.999). Enrichment analyses indicated involvement of implicated proteins in Toll-like receptor signaling and T-helper 17 cell differentiation pathways. This study identified several CIPs - including TNF-β, osteoprotegerin, and adenosine deaminase - as potentially causal in OM development. These findings highlight promising targets for future immunomodulatory therapies aimed at preventing or mitigating osteomyelitis.

Humans↗

PubMed2026

Proteomic patterns according to ejection fraction: an EMPEROR-programme analysis.

AIMS: Left ventricular ejection fraction (LVEF) has been incorporated as an inclusion criterion in HF trials. Patient's characteristics, event risk, and treatment response vary according to LVEF. A better understanding of the biological processes across LVEF is warranted. To study proteomic biomarker expression across LVEF using data from the EMPEROR-Programme. METHODS: Two thousand two hundred and fifty-four patients who had proteomic measurements available using 1134 proteins overlapping between the Explore 1536 and 3072 Olink® platforms were included. Main analyses were performed within the EMPEROR-Preserved dataset due to differences in entry criteria between EMPEROR-Preserved and EMPEROR-Reduced with higher entry N-terminal pro B-type natriuretic peptide (NT-proBNP) levels that varied by LVEF cut-offs in the latter. Protein concentrations were compared using ordinal logistic regression across LVEF categories: 41%-49%, 50%-59%, and ≥60%. The resulting β-coefficient indicates the change in the log-odds for the outcome of being in a lower LVEF category for every NPX unit in log2 scale. Analyses were adjusted for covariates and a false-discovery-rate (FDR) correction was applied. RESULTS: A total of 297 proteins exhibited a trend of expression across LVEF categories in EMPEROR-Preserved after adjustment for potential confounders and correction for test multiplicity. Of these, the top 10 proteins were: NT-pro BNP (β = 0.18, 95% CI 0.09-0.27), Wnt inhibitory factor-1 (β = 0.40, 95% CI 0.19-0.61), sialomucin core protein 24 (β = 0.48, 95% CI 0.22-0.74), phospholipid transfer protein (β = 0.38, 95% CI 0.17-0.59), natriuretic peptides B (β = 0.13, 95% CI 0.06-0.20), intercellular adhesion molecule 5 (β = 0.31, 95% CI 0.14-0.49), neural cell adhesion molecule 2 (β = 0.45, 95% CI 0.19-0.70), neural cell adhesion molecule L1-like protein (β = 0.45, 95% CI 0.19-0.71), interactor protein for cytohesin exchange factors 1 (β = 0.12, 95% CI 0.05-0.19), and 3-ketoacyl-CoA thiolase, peroxisomal (β = 0.17, 95% CI 0.07-0.26). The correlation between these proteins and LVEF was generally weak (Rho ≤0.2). CONCLUSIONS: Within EMPEROR-Preserved, the top differentially expressed circulating proteins suggest that pathways related to natriuretic peptides, cell-adhesion, and clonal haematopoiesis are overexpressed at mildly-reduced ejection fraction, but none of the proteins passed the 5%FDR cut-off, and the correlation between circulating proteins and LVEF was weak. These findings suggest that circulating proteins may not be a good discriminant of ejection fraction.

Humans↗

PubMed2026

Protein mediators of chronic kidney disease in Type 2 diabetes: A mendelian randomization study.

BACKGROUND: Chronic kidney disease (CKD) occurs in 20-50% of the people living with Type 2 diabetes (T2D) and is the leading cause of kidney failure worldwide. The cause of CKD is not fully understood, and few interventions prevent CKD in individuals living with diabetes. Here, we use large-scale proteomics data to identify circulating proteins that mediate the relationship between T2D and kidney disorders. METHODS AND FINDINGS: First, we used two-sample mendelian randomization (MR) and identified 71 circulating proteins whose levels were altered by genetic predisposition to T2D based on circulating proteomic GWAS from deCODE with 35,559 individuals and T2D GWAS with 80,154 cases. Then, we used cis-genetic variants to proxy the causal effect of some of these T2D-influenced circulating proteins and found that, collectively, five proteins (INHBC, GNPTG, LPO, AGRN, and CTSD) affected three kidney traits (blood urea nitrogen [BUN], estimated glomerular filtration rate [eGFR] and CKD risk) based on GWAS with up to 1,004,040 participants. Notably, we found that higher levels of circulating INHBC protein were estimated to lead to a lower eGFR and higher BUN based on MR analyses. We then replicated this MR analysis with proteomic GWAS from four additional cohorts, namely, UKB-PPP, Fenland, ARIC, and EPIC-Norfolk. We observed a consistent direction of effect across all four proteomic GWAS datasets, supporting the robustness of our results against platform and cohort variation. In observational analyses, increased circulating INHBC levels were associated with increased hazard for kidney disease diagnosis in 37,854 UK Biobank participants. We estimated that circulating INHBC levels mediate 1.3% (95% confidence interval [0.85%, 1.9%]) of the association between T2D and kidney disease diagnosis. There are important limitations in this study. Firstly, although we observed limited evidence for violations to the MR assumptions, some are untestable. Secondly, our study was not based on individuals with diabetic kidney diseases, but rather independent population-based studies assessing diabetes and kidney function separately. Therefore, additional functional analyses in disease specific cohort are needed. CONCLUSIONS: Collectively, these findings suggest that T2D influences the risk of CKD, in part, through increased circulating INHBC levels.

Humans↗

PubMed2026

Exploring Causal Links Between 91 Circulating Inflammatory Proteins and Hashimoto's Thyroiditis: A Bidirectional Mendelian Randomization Study.

BACKGROUND: Increasing evidence has linked inflammation to Hashimoto's thyroiditis (HT) etiology. However, the causal role of circulating inflammatory proteins in HT remains uncertain. To investigate this, we conducted a bidirectional Mendelian randomization (MR) study. METHODS: Genetic data for 91 inflammatory proteins and HT were sourced from publicly available GWAS databases. The PhenoScanner database was then searched for pleiotropic SNPs associated with potential confounders. Inverse variance weighted (IVW) analysis was used as the primary analysis, simultaneously supplemented by five sensitivity analyses to strengthen the results. RESULTS: The results revealed that, after false discovery rate (FDR) correction, interleukin (IL)-12p40 was causally associated with increased risk of HT (OR [95% CI] = 1.295 [1.172, 1.431], p = 3.66 × 10-7, PFDR = 3.33×10-5). Conversely, none of the inflammatory proteins was a consequence of HT. CONCLUSION: This study suggests that IL-12p40 is probably one of the factors correlated with HT etiology, contributing to a better understanding of the pathogenesis of HT and underscoring the potential for therapeutic interventions targeting inflammatory proteins.

Humans↗

PubMed2025

Integrative proteomic analysis provides novel therapeutic insights for etiological subtypes of diabetes.

AIMS: Type 2 diabetes (T2D) is a highly heterogeneous disease characterised by subtypes with variations in aetiology, disease progression, and risk of complications. However, potential drug targets for these subtypes have not been explored. This study aims to investigate potential drug targets by integrating proteomics. MATERIALS AND METHODS: Summary-level data of circulating proteins were extracted from the UK Biobank and the deCODE Health Study. Genetic associations with five diabetes subtypes were obtained from Swedish All New Diabetics in Scania and Malmö Diet and Cancer cohort, including severe autoimmune diabetes (SAID), severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD), and mild age-related diabetes (MARD). The associations between circulating proteins and diabetes subtypes were assessed through Mendelian randomisation, followed by multiple sensitivity and colocalization analyses. Additionally, tissue-specific, pathway and functional enrichment analysis, assessment of protein druggability, and the protein-protein interaction (PPI) networks were used to further explore biological mechanisms and therapeutic potential. RESULTS: Genetically predicted levels of 2, 2, 9, 3, and 5 circulating proteins were associated with SIRD, SIDD, MARD, MOD, and SAID, respectively. Colocalization analyses further revealed links between GRN with MARD/SIRD, LILRB5 with SIDD/MARD, CR1 with MARD, TNFSF12 with MOD, and DAPK2 with SAID. Enrichment analysis suggested that these proteins were mainly enriched in blood and adipose tissues and involved in immune and inflammatory related pathways. PPI analysis revealed GRN, TNFSF12, and DAPK2 are associated with known T2D targets. CONCLUSIONS: Our study identified several potential drug targets for different subtypes of diabetes using an integrated genetic approach, yielding new insights for precision medicine of diabetes.

Humans↗

PubMed2026

Identification and genetic validation of potential therapeutic targets for pulmonary hypertension through multi-omics causal inference.

Pulmonary hypertension (PH) underscores the urgent need for novel therapeutic targets. This study aimed to employ a proteome-wide Mendelian randomization (MR) approach to systematically identify circulating proteins causally associated with PH, thereby providing genetically validated candidate targets for drug development. We adopted a 2-sample MR design, integrating large-scale plasma proteomic quantitative trait loci (pQTL) data (encompassing 4148 proteins) and summary statistics from a large-scale PH genome-wide association study (2047 cases, 8301 controls). Candidate targets were screened through a multilayered analytical pipeline comprising proteomic MR, transcriptomic MR, and summary-data-based Mendelian randomization. The ultimately identified MR-Identified Causal Candidate Targets (MR-ICTs) underwent rigorous Bayesian colocalization analysis, followed by biological characterization through functional enrichment analysis, single-cell transcriptomics, and phenome-wide association studies. Through robust genetic causal inference, this study provides that circulating proteins such as LYZ, GREM2, NID1, and PF4V1 play causal roles in PH pathogenesis. These findings offer a set of rigorously genetically validated, high-priority therapeutic targets for developing novel PH treatments, specifically addressing key pathological mechanisms such as innate immunity, BMP signaling pathway dysregulation, and platelet activation. Our multi-dimensional analysis ultimately identified 6 MR-ICTs causally associated with PH. Notably, the causal associations for lysozyme C (LYZ), gremlin-2 (GREM2), nidogen-1 (NID1), and platelet factor 4 variant 1 (PF4V1) were stringently validated by Bayesian colocalization analysis (posterior probability for hypothesis 4 [PPH4], indicating a shared causal variant, > 0.99). Functional enrichment analysis revealed significant involvement of these targets in immune response and TGF-β signaling pathways. Single-cell analysis further elucidated their cell-type-specific expression, with LYZ predominantly expressed in monocytes and PF4V1 almost exclusively in platelets.

Hypertension, Pulmonary↗

PubMed1976

Plasma volume changes after infusion of various plasma expanders.

In the immediate post-operative period after moderate surgical procedures, 1 litre of a colloid solution or saline was given intravenously. The plasma volume expansion after infusion of dextran 70 (Macrodex), hydroxyethylstarch (Volex), polygelatin (Haemaccel), albumin and saline was found to be between 790 and 180 ml. The most efficent plasma expander was dextran, followed by hydroxyethylstarch. Polygelatin and saline did not give full restitution, although twice the calculated loss was infused. Total plasma protein concentration was lowered in all groups in proportion to the dilution, except for the patients given albumin, in whom the concentration of total protein increased. Calculation of the total circulating protein mass showed no decrease during the period immediately after the infusion. This investigation has demonstrated that the most efficient plasma volume expander is dextran but that hydroxyethylstarch offers an almost equal alternative in terms of volume expansion. Dextran, however, exerts an advantageous effect on the microcirculation. As the metabolic pathways of hydroxyethylstarch have not yet been further explored, dextran is preferred when using artificial colloids. Judged by its secondary effects alone, including the influence on plasma protein patterns, albumin seems to be the compound of choice. Polygelatin and saline are not efficient expanders when hypovolaemia is to be corrected rapidly.

Adult↗

PubMed1978

Circulating lymphocytes and the spread of myeloma. Review of the evidence.

Patients with myeloma harbour circulating lymphocytes which bear the idiotypic determinants (SIg-id+ cells) of their own myeloma protein. Circulating white cells with abnormal karyotypes have been found in other patients with this disease. SIg-id+ lymphocytes have also been identified in the peripheral blood of myeloma-tumour-bearing mice. Murine myelomas have been propagated in vivo from circulating mononuclear cells that possessed myeloma-tumour-associated antigens. This and other evidence reviewed here points strongly to the involvement of circulating lymphocyte-like stem cells in the spread of human myeloma.

Animals↗

PubMed2025

Admixture-mapping analysis reveals genetic determinants of the human plasma proteome.

Protein profiling and genetic findings can be integrated to define the genetic architecture of the circulating proteome in chronic diseases. Most self-identified African American (AA) individuals have both African and European genetic ancestry. Admixture mapping can detect genomic association regions in which causal variants exist with substantial differences in allele frequency or effect sizes between genetic ancestries. We performed admixture mapping of the circulating proteome in 1,989 participants from the Jackson Heart Study (JHS), investigating the relation of local African ancestry within genomic regions with levels of circulating proteins. We conditioned protein-local ancestry association models on variants previously found to be associated with those proteins in genome-wide association studies (GWASs). We replicated findings in 196 AA participants from the Multi-Ethnic Study of Atherosclerosis (MESA). 62 proteins were associated with local African ancestry. 21 of 62 remained statistically significant after conditioning on protein-associated variants observed in previous GWASs. 48 of 54 available protein-local ancestry associations were replicated in the MESA. Proteins associated with local African ancestry included chemokines, factors associated with vascular biology and inflammation, and other biologically interesting proteins. Admixture associations unexplained by previously reported protein-associated variants in conditional analysis suggest the existence of causal variants missed by standard GWAS techniques.

Aged↗

PubMed1975

A study of the influence of various antirheumatic drug regimens on serum acute-phase proteins, plasma tryptophan, and erythrocyte sedimentation rate in rheumatoid arthritis.

In patients with rheumatoid arthritis neither indomethacin nor aspirin influenced the levels of the erythrocyte sedimentation rate (e.s.r) or serum acute-phase proteins fibrinogen, haptoglobin, C-reactive protein and alphaI acid-glycoprotein). Treatment with D-penicillamine, sodium aurothiomalate, or alclofenac produced a significant reduction both in acute-phase protein levels and in e.s.r. Each of the drugs displaced L-tryptophan from plasma proteins in vivo but withdrawal of indomethacin and aspirin was followed immediatley by excessive binding of this amino acid to circulating proteins:this phenomenon was not observed when alclofenac, sodium aurothiomalate or D-penicillamine were withdrawn. It has been demonstrated that disease activity in rheumatoid arthritis is reflected in acute-phase protein concentrations and in the extent to which L-tryptophan is bount to plasma protein. It is suggested that drugs which profoundly affect these parameters provide not only symptomatic relieft but also possible beneficial effects upon the disease process itself.

Adult↗

PubMed1977

Heterogeneity of the cold-insoluble globulin of human plasma (CIg), a circulating cell surface protein.

The cold-insoluble globulin of human plasma (CIg), a circulating cell surface protein, exists in multiple molecular forms. Most molecules are found as two chain (MR approximately 220 000 per chain) disulfide-bridged dimeric units but several minor components of smaller size have also been identified; based upon their migration rates in dodecyl sulfate gel electrophoretic experiments, the smaller molecules characterized in this study range in molecular size from 235 000 to 146 000. The component of molecular weight 235 000 apparently represents a two chain disulfide-bridged derivative of larger parent molecules (one chain of 220 000 plus a smaller remnant), whereas smaller CIg components appear to be single chain proteins. These observations plus electrophoretic analyses of samples of plasmic digests of CIg indicate that the interchain disulfide bridging in the two chain molecule is located in a segment within approx. 175 residues of the NH2- or COOH-terminus.

Dithiothreitol↗

PubMed2026

Characterizing the impact of plasma protein levels on human brain structure and disorders leveraging integrative multi-omics analysis.

With recent advances in high-throughput proteomic technologies, population-scale plasma proteomics datasets, often linked to extensive genetic and phenotypic information, have become increasingly accessible. Yet the relationships between circulating protein levels, brain imaging phenotypes, and risk for neurological and psychiatric disorders remain largely unexplored. Proteome-wide association studies offer a promising approach for elucidating biological mechanisms that connect genetic variation to complex brain-related traits and diseases. In this study, we integrated protein quantitative trait loci (pQTLs) from the two largest plasma proteomic resources (the UK Biobank Pharma Proteomics Project [UKB-PPP] and Ferkingstad et al. [deCODE]) with genome-wide association studies of brain imaging-derived phenotypes in UK Biobank using Mendelian randomization and colocalization analyses. We identified 120 cis and 20 trans associations between plasma proteins and imaging phenotypes and validated these findings using brain tissue-derived proteomic and transcriptomic datasets. Multivariable Mendelian randomization revealed eleven plasma proteins (coding genes APOE, ARL3, MICB, NSF, RHOC, RSPO3, ENPP2, BTN2A1, EIF2AK3, MRVI1, and OPLAH) with significant direct effects on the risk of Alzheimer's disease, Parkinson's disease, multiple sclerosis, bipolar disorder, and schizophrenia. Single-cell expression and pathway enrichment analyses further revealed cell-type-specific effects and distinct biological processes underlying these protein-disease associations. Together, these findings demonstrate robust links between plasma protein variation and brain structure, delineate protein-disease pathways, and highlight the cellular and molecular mechanisms that contribute to neurobiological diversity and pathology.

Journal Article↗

PubMed2026

Large-Scale Plasma Proteomics Identifies Early Molecular Deviations and Improves Risk Prediction for Heart Failure Among Individuals With Obesity.

AIMS: Heart failure (HF) is a major global public health challenge, with obesity being one of its key risk factors. Although several HF risk prediction models have been developed in the general population, few are specifically tailored to individuals with obesity. This underscores the urgent need for precise biomarkers to improve individual risk stratification and enable personalized prevention strategies. We aimed to develop and validate a plasma proteomics-based protein risk score (PRS) to predict incident HF among individuals with obesity. MATERIALS AND METHODS: We analysed 9831 participants with obesity (BMI ≥ 30 kg/m2) from the UK Biobank with baseline measurements of 2911 circulating proteins and up to 16 years of follow-up. Multivariable Cox regression identified proteins associated with incident HF after comprehensive covariate adjustment. A PRS was constructed using LASSO regression and evaluated in a held-out test set. Protein trajectories before HF onset were reconstructed using LOESS modelling. To enhance clinical feasibility, a minimal protein panel was identified using LightGBM with forward feature selection. RESULTS: A total of 727 participants developed HF during follow-up. Multivariable cox analyses identified 578 proteins significantly associated with HF. LASSO regression further selected 81 proteins to build the PRS, which showed a strong association with HF risk in both training (HR 3.57; 95% CI 3.19-4.00) and test cohorts (HR 2.45; 95% CI 2.20-2.74). Adding the PRS improved prediction beyond age and sex (ΔC = 0.091) and beyond the Pooled Cohort Equations to Prevent Heart Failure (PCP-HF) model (ΔC = 0.052), with consistent gains in NRI and IDI. Proteomic deviations were detectable up to 16 years before diagnosis. A four-protein panel (GDF15, NT-proBNP, TNFRSF10B, CTHRC1) achieved robust discrimination (AUC 0.789), outperforming NT-proBNP alone (AUC 0.695) and complementing the PCP-HF model (combined AUC 0.803). DISCUSSION: Large-scale plasma proteomics substantially improves HF risk prediction in individuals with obesity and reveals long-standing molecular alterations preceding clinical onset. A simplified four-protein panel maintains robust predictive accuracy and provides a practical approach for the early detection and targeted prevention of obesity-related HF.

Humans↗

PubMed2026

GWAS Meta-analysis Identifies Novel Associated Loci and Points to Causal Tissues in Central Serous Chorioretinopathy.

OBJECTIVE: To define CSC genetic architecture and identify implicated ocular tissues, cell types, genes, and circulating proteins. DATA SOURCES: Genome-wide data were assembled from FinnGen, All of Us, Mass General Brigham Biobank, Million Veteran Program, and a Dutch chronic CSC cohort. Serum protein quantitative trait loci, human single-cell ocular atlases, and UK Biobank macular optical coherence tomography (OCT) imaging were used for downstream analyses. STUDY SELECTION: Five European-ancestry cohorts with genome-wide data and cohort-specific CSC case-control definitions were included, comprising 2,584 cases and 1,044,455 controls. Variants present in at least 2 cohorts were meta-analyzed. DATA EXTRACTION AND SYNTHESIS: Cohort-level GWASs were adjusted for age, age squared, sex, genotyping array or batch, and 10 genetic principal components, then combined using fixed-effects inverse-variance meta-analysis. Post-GWAS analyses included gene prioritization, colocalization, Mendelian randomization, single-cell disease-relevance scoring, and testing of a CSC genetic risk score in UK Biobank OCT images. MAIN OUTCOMES AND MEASURES: Genome-wide significant CSC loci, effector genes and proteins, tissue and cell-type enrichment, and CSC-relevant OCT abnormalities. RESULTS: Across 11,068,938 variants, 10 loci reached genome-wide significance (P < 5 × 10-8), including 3 novel loci near TGFB1, LINC00551, and LOC105375630 and 7 replicated loci near CFH, CD46, NOTCH4, PREX1, PTPRB, GATA5, and TNFRSF10A. Integrative analyses prioritized 10 candidate effector genes. Colocalization and Mendelian randomization implicated circulating TNFRSF10A, TGFB1, and CASP10 levels. Single-cell analyses localized genetic risk to sclera (P = 2.0 × 10-4) and vascular endothelial cells (P = 4.0 × 10-4), with fibroblast enrichment. In UK Biobank, OCT abnormalities were more frequent in the top vs bottom 1% of CSC genetic risk (18 of 109 [16.5%] vs 8 of 134 [6.0%]; odds ratio, 4.05; 95% CI, 1.65-10.87; P = .002). CONCLUSIONS AND RELEVANCE: In this GWAS meta-analysis, CSC susceptibility localized predominantly to scleral and vascular biology rather than primary retinal pigment epithelial dysfunction. These findings support CSC as a sclerovascular disorder and nominate complement regulation, endothelial signaling, and extracellular matrix pathways for future study.

Journal Article↗