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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Stroke genetics informs drug discovery and risk prediction across ancestries

Nature, Journal Year: 2022, Volume and Issue: 611(7934), P. 115 - 123

Published: Sept. 30, 2022

Previous genome-wide association studies (GWASs) of stroke - the second leading cause death worldwide were conducted predominantly in populations European ancestry1,2. Here, cross-ancestry GWAS meta-analyses 110,182 patients who have had a (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify signals for its subtypes at 89 (61 new) independent loci: 60 primary inverse-variance-weighted analyses 29 secondary meta-regression multitrait analyses. On basis internal validation an follow-up 89,084 additional cases (30% 1,013,843 87% risk loci 60% replicated (P < 0.05). Effect sizes highly correlated across ancestries. Cross-ancestry fine-mapping, silico mutagenesis analysis3, transcriptome-wide proteome-wide revealed putative causal genes (such as SH3PXD2A FURIN) variants GRK5 NOS3). Using three-pronged approach4, provide genetic evidence drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 VCAM1 possible targets, with drugs already under investigation F11 PROC. A polygenic score integrating ancestry-specific GWASs vascular-risk factor (integrative scores) strongly predicted ischaemic European, East Asian African ancestry5. Stroke scores predictive clinical factors 52,600 clinical-trial participants cardiometabolic disease. Our results insights to inform biology, reveal potential targets derive prediction tools

Language: Английский

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Measuring biological age using omics data

Nature Reviews Genetics, Journal Year: 2022, Volume and Issue: 23(12), P. 715 - 727

Published: June 17, 2022

Language: Английский

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Combining evidence from Mendelian randomization and colocalization: Review and comparison of approaches

The American Journal of Human Genetics, Journal Year: 2022, Volume and Issue: 109(5), P. 767 - 782

Published: April 21, 2022

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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TTD: Therapeutic Target Database describing target druggability information

Nucleic Acids Research, Journal Year: 2023, Volume and Issue: 52(D1), P. D1465 - D1477

Published: Sept. 15, 2023

Target discovery is one of the essential steps in modern drug development, and identification promising targets fundamental for developing first-in-class drug. A variety methods have emerged target assessment based on druggability analysis, which refers to likelihood a being effectively modulated by drug-like agents. In therapeutic database (TTD), nine categories established characteristics were thus collected 426 successful, 1014 clinical trial, 212 preclinical/patented, 1479 literature-reported via systematic review. These characteristic classified into three distinct perspectives: molecular interaction/regulation, human system profile cell-based expression variation. With rapid progression technology concerted effort discovery, TTD other databases highly expected facilitate explorations validation innovative target. now freely accessible at: https://idrblab.org/ttd/.

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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Multiomics study of nonalcoholic fatty liver disease

Nature Genetics, Journal Year: 2022, Volume and Issue: 54(11), P. 1652 - 1663

Published: Oct. 24, 2022

Nonalcoholic fatty liver (NAFL) and its sequelae are growing health problems. We performed a genome-wide association study of NAFL, cirrhosis hepatocellular carcinoma, integrated the findings with expression proteomic data. For we utilized 9,491 clinical cases proton density fat fraction extracted from 36,116 magnetic resonance images. identified 18 sequence variants associated NAFL 4 cirrhosis, found rare, protective, predicted loss-of-function in MTARC1 GPAM, underscoring them as potential drug targets. leveraged messenger RNA expression, splicing coding effects to identify 16 putative causal genes, which many implicated lipid metabolism. analyzed levels 4,907 plasma proteins 35,559 Icelanders 1,459 47,151 UK Biobank participants, identifying multiple involved disease pathogenesis. show that proteomics can discriminate between cirrhosis. The present provides insights into development noninvasive evaluation new therapeutic options.

Language: Английский

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