Plasma proteomic associations with genetics and health in the UK Biobank

Nature, Journal Year: 2023, Volume and Issue: 622(7982), P. 329 - 338

Published: Oct. 4, 2023

The Pharma Proteomics Project is a precompetitive biopharmaceutical consortium characterizing the plasma proteomic profiles of 54,219 UK Biobank participants. Here we provide detailed summary this initiative, including technical and biological validations, insights into disease signatures, prediction modelling for various demographic health indicators. We present comprehensive protein quantitative trait locus (pQTL) mapping 2,923 proteins that identifies 14,287 primary genetic associations, which 81% are previously undescribed, alongside ancestry-specific pQTL in non-European individuals. study provides an updated characterization architecture proteome, contextualized with projected discovery rates as sample sizes assay coverages increase over time. offer extensive trans pQTLs across multiple domains, highlight influences on ligand-receptor interactions pathway perturbations diverse collection cytokines complement networks, illustrate long-range epistatic effects ABO blood group FUT2 secretor status gastrointestinal tissue-enriched expression. demonstrate utility these data drug by extending proxied targets, such PCSK9, additional endpoints, disentangle specific genes perturbed at loci associated COVID-19 susceptibility. This public-private partnership scientific community open-access proteomics resource considerable breadth depth to help elucidate mechanisms underlying proteo-genomic discoveries accelerate development biomarkers, predictive models therapeutics

Language: Английский

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Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets

Nature Immunology, Journal Year: 2023, Volume and Issue: 24(9), P. 1540 - 1551

Published: Aug. 10, 2023

Circulating proteins have important functions in inflammation and a broad range of diseases. To identify genetic influences on inflammation-related proteins, we conducted genome-wide protein quantitative trait locus (pQTL) study 91 plasma measured using the Olink Target platform 14,824 participants. We identified 180 pQTLs (59 cis, 121 trans). Integration pQTL data with eQTL disease association studies provided insight into pathogenesis, implicating lymphotoxin-α multiple sclerosis. Using Mendelian randomization (MR) to assess causality etiology, both shared distinct effects specific across immune-mediated diseases, including directionally discordant CD40 risk rheumatoid arthritis versus sclerosis inflammatory bowel disease. MR implicated CXCL5 etiology ulcerative colitis (UC) show elevated gut transcript expression patients UC. These results targets existing drugs provide powerful resource facilitate future drug target prioritization.

Language: Английский

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The next-generation Open Targets Platform: reimagined, redesigned, rebuilt

Nucleic Acids Research, Journal Year: 2022, Volume and Issue: 51(D1), P. D1353 - D1359

Published: Nov. 18, 2022

The Open Targets Platform (https://platform.opentargets.org/) is an open source resource to systematically assist drug target identification and prioritisation using publicly available data. Since our last update, we have reimagined, redesigned, rebuilt the in order streamline data integration harmonisation, expand ways which users can explore data, improve user experience. gene-disease causal evidence has been enhanced expanded better capture disease causality across rare, common, somatic diseases. For annotations, incorporated new features that help assess safety tractability, including genetic constraint, PROTACtability assessments, AlphaFold structure predictions. We also introduced machine learning applications for knowledge extraction from published literature, clinical trial information, labels. technologies frameworks since update will ease introduction of creation separate instances adapted requirements. Our Community forum, training materials, outreach programme support a range use cases.

Language: Английский

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Plasma proteome analyses in individuals of European and African ancestry identify cis-pQTLs and models for proteome-wide association studies

Nature Genetics, Journal Year: 2022, Volume and Issue: 54(5), P. 593 - 602

Published: May 1, 2022

Language: Английский

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Large-scale plasma proteomics comparisons through genetics and disease associations

Nature, Journal Year: 2023, Volume and Issue: 622(7982), P. 348 - 358

Published: Oct. 4, 2023

High-throughput proteomics platforms measuring thousands of proteins in plasma combined with genomic and phenotypic information have the power to bridge gap between genome diseases. Here we performed association studies Olink Explore 3072 data generated by UK Biobank Pharma Proteomics Project

Language: Английский

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Potential drug targets for multiple sclerosis identified through Mendelian randomization analysis

Brain, Journal Year: 2023, Volume and Issue: 146(8), P. 3364 - 3372

Published: March 1, 2023

Multiple sclerosis is a complex autoimmune disease, and several therapies for multiple have been developed widely used. However, existing medications were far from satisfactory due to their failure suppress relapses alleviate disease progression. Novel drug targets prevention are still needed. We performed Mendelian randomization explore potential using summary statistics the International Sclerosis Genetics Consortium (nCase = 47 429, nControl 68 374) further replicated in UK Biobank 1356, 395 209) FinnGen cohorts 1326, 359 815). Genetic instruments 734 plasma 154 CSF proteins obtained recently published genome-wide association studies. The reverse causality detection bidirectional analysis Steiger filtering, Bayesian co-localization, phenotype scanning that searched previously reported genetic variant-trait associations implemented consolidate findings further. In addition, protein-protein interaction network was reveal among and/or present medications. At Bonferroni significance (P < 5.63 × 10-5), revealed six protein-multiple pairs. plasma, per standard deviation increase FCRL3, TYMP AHSG had protective effect. Odds ratios above 0.83 (95% CI, 0.79-0.89), 0.59 0.48-0.71) 0.88 0.83-0.94), respectively. CSF, 10-fold MMEL1 (OR, 5.03; 95% 3.42-7.41) increased risk of sclerosis, while SLAMF7 0.42; 0.29-0.60) CD5L 0.30; 95%CI, 0.18-0.52) decreased risk. None causality. co-localization suggested FCRL3 [coloc.abf-posterior probability hypothesis 4 (PPH4) 0.889], (coloc.susie-PPH4 0.896), (coloc.abf-PPH4 0.957, coloc.susie-PPH4 0.973), 0.930) 0.947) shared same variant with sclerosis. interacted target current both cohorts. Our integrative genetically determined levels circulating TYMP, AHSG, causal effects on These those five might be promising warrant clinical investigation, especially SLAMF7.

Language: Английский

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Synergistic insights into human health from aptamer- and antibody-based proteomic profiling

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: Nov. 24, 2021

Abstract Affinity-based proteomics has enabled scalable quantification of thousands protein targets in blood enhancing biomarker discovery, understanding disease mechanisms, and genetic evaluation drug humans through quantitative trait loci (pQTLs). Here, we integrate two partly complementary techniques—the aptamer-based SomaScan ® v4 assay the antibody-based Olink assays—to systematically assess phenotypic consequences hundreds pQTLs discovered for 871 across both platforms. We create a genetically anchored cross-platform proteome-phenome network comprising 547 protein–phenotype connections, 36.3% which were only seen with one platforms suggesting that techniques capture distinct aspects biology. further highlight discordance predicted effect directions between assays, such as PILRA Alzheimer’s disease. Our results showcase synergistic nature these technologies to better understand identify mechanisms provide benchmark future discoveries.

Language: Английский

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Assessment of variability in the plasma 7k SomaScan proteomics assay

Scientific Reports, Journal Year: 2022, Volume and Issue: 12(1)

Published: Oct. 13, 2022

SomaScan is a high-throughput, aptamer-based proteomics assay designed for the simultaneous measurement of thousands proteins with broad range endogenous concentrations. In its most current version, 7k v4.1 capable measuring 7288 human proteins. this work, we present an extensive technical assessment platform based on study 2050 samples across 22 plates. Included in design were inter-plate duplicates from 102 subjects, which allowed us to characterize different normalization procedures, evaluate variability by multiple analytical approaches, signal-over-background metrics, and discuss potential specificity issues. By providing detailed performance assessments wide aspects, aim work serve as valuable resource growing community users.

Language: Английский

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Genetic regulation of the human plasma proteome in 54,306 UK Biobank participants

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: June 18, 2022

Abstract The UK Biobank Pharma Proteomics Project (UKB-PPP) is a collaboration between the (UKB) and thirteen biopharmaceutical companies characterising plasma proteomic profiles of 54,306 UKB participants. Here, we describe results from first phase UKB-PPP, including protein quantitative trait loci (pQTL) mapping 1,463 proteins that identifies 10,248 primary genetic associations, which 85% are newly discovered. We also identify independent secondary associations in 92% cis 29% trans loci, expanding catalogue instruments for downstream analyses. study provides an updated characterisation architecture proteome, leveraging population-scale proteomics to provide novel, extensive insights into pQTLs across multiple biological domains. highlight influences on ligand-receptor interactions pathway perturbations diverse collection cytokines complement proteins, illustrate long-range epistatic effects ABO blood group FUT2 secretor status with gastrointestinal tissue-enriched expression. demonstrate utility these data drug target discovery by extending proxied effect PCSK9 levels lipid concentrations, cardio- cerebro-vascular diseases, additionally disentangle specific genes perturbed at COVID-19 susceptibility loci. This public-private partnership scientific community open-access resource unprecedented breadth depth help elucidate mechanisms underlying discoveries accelerate development novel biomarkers therapeutics.

Language: Английский

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Identification of novel protein biomarkers and drug targets for colorectal cancer by integrating human plasma proteome with genome

Genome Medicine, Journal Year: 2023, Volume and Issue: 15(1)

Published: Sept. 19, 2023

Abstract Background The proteome is a major source of therapeutic targets. We conducted proteome-wide Mendelian randomization (MR) study to identify candidate protein markers and targets for colorectal cancer (CRC). Methods Protein quantitative trait loci (pQTLs) were derived from seven published genome-wide association studies (GWASs) on plasma proteome, summary-level data extracted 4853 circulating markers. Genetic associations with CRC obtained large-scale GWAS meta-analysis (16,871 cases 26,328 controls), the FinnGen cohort (4957 304,197 UK Biobank (9276 477,069 controls). Colocalization summary-data-based MR (SMR) analyses performed sequentially verify causal role proteins. Single cell-type expression analysis, protein-protein interaction (PPI), druggability evaluation further detect specific cell type enrichment prioritize potential Results Collectively, genetically predicted levels 13 proteins associated risk. Elevated two (GREM1, CHRDL2) decreased 11 an increased risk CRC, among which four CLSTN3, CSF2RA, CD86) prioritized most convincing evidence. These protein-coding genes are mainly expressed in tissue stem cells, epithelial monocytes colon tumor tissue. Two interactive pairs (GREM1 CHRDL2; MMP2 TIMP2) identified be involved osteoclast differentiation tumorigenesis pathways; (POLR2F, CD86, MMP2) have been targeted drug development autoimmune diseases other cancers, potentials being repurposed as CRC. Conclusions This several biomarkers provided new insights into etiology promising screening drugs

Language: Английский

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