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

Zhang, Jingning; Dutta, Diptavo; Köttgen, Anna; Tin, Adrienne; Schlosser, Pascal; Grams, Morgan E.; Harvey, Benjamin; Yu, Bing; Boerwinkle, Eric; Chatterjee, Nilanjan

doi:10.1038/s41588-022-01051-w

Cited by 196 publications

(256 citation statements)

References 87 publications

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“…Thus, the present study and its expansion project will likely miss important insights in non-European individuals. We encourage prospective users of these data to integrate additional proteogenomic data from under-represented populations 76 , and strongly recommend that future investments in population proteomics prioritize genetic diversity in their cohort selection(s) 77 .…”

Section: Discussionmentioning

confidence: 99%

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

Sun

Chiou

Traylor

et al. 2022

Preprint

117

194

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

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Section: Discussionmentioning

confidence: 99%

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

Sun

Chiou

Traylor

et al. 2022

Preprint

117

194

View full text Add to dashboard Cite

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“…The circulating levels of proteins and expression levels of genes were selected as exposures in this study since they represent drug targets for many drugs. To generate genetic instruments for potential drug targets, genetic variants robustly associated with the levels of proteins and gene transcripts (with P < 5 × 10 −8 ), irrespective of genomic position of variants, were selected from six proteome datasets extracted from two studies 13 , 16 and two transcriptome datasets. 28 , 29 …”

Section: Methodsmentioning

confidence: 99%

“…For pQTL instruments, 272 of 5326 (5.1%) of the instruments in European ancestry and 54 of 3543 (1.5%) variants in African ancestry were in low to modest LD (r 2 between 0.2 to 0.6; Table S1A and 1B). These pQTLs were obtained from Zhang et al, 16 which were conditional independent pQTL signals after conditional analysis and genetic fine mapping. More details of the instrument selection were described in Note S1.…”

Section: Methodsmentioning

confidence: 99%

“…Recent multi-ancestry genetic studies have further showcased the value of omics analyses in predicting treatment response in various populations. 16 , 17 …”

Section: Introductionmentioning

confidence: 99%

“…The aim of this study was to prioritise potential drug targets for COVID-19 severity as well as to identify potential beneficial and adverse effects of these targets on other diseases. We combined genetic association information on 16,059 transcripts and 1608 proteins in European ancestry 13 , 28 , 29 and 610 proteins in African ancestry, 16 and applied a recent omics MR analysis pipeline 17 to estimate the causal effects of these targets on COVID-19 severity in the two ancestries separately. To enable rapid queries, results of all analyses are available in an open access online platform ( https://epigraphdb.org/covid-19/ctda/ ).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Multi-ancestry Mendelian randomization of omics traits revealing drug targets of COVID-19 severity

Zheng¹,

Zhang²,

Zhao³

et al. 2022

eBioMedicine

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Plasma Proteomics of Exercise Blood Pressure and Incident Hypertension

Rao,

Keyes,

et al. 2024

JAMA Cardiol

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ImportanceBlood pressure response during acute exercise (exercise blood pressure [EBP]) is associated with the future risk of hypertension and cardiovascular disease (CVD). Biochemical characterization of EBP could inform disease biology and identify novel biomarkers of future hypertension.ObjectiveTo identify protein markers associated with EBP and test their association with incident hypertension.Design, Setting, and ParticipantsThis study assayed 4977 plasma proteins in 681 healthy participants (from 763 assessed) of the Health, Risk Factors, Exercise Training and Genetics (HERITAGE; data collection from January 1993 to December 1997 and plasma proteomics from January 2019 to January 2020) Family Study at rest who underwent 2 cardiopulmonary exercise tests. Individuals were free of CVD at the time of recruitment. Individuals with resting SBP ≥160 mm Hg or DBP ≥100 mm Hg or taking antihypertensive drug therapy were excluded from the study. The association between resting plasma protein levels to both resting BP and EBP was evaluated. Proteins associated with EBP were analyzed for their association with incident hypertension in the Framingham Heart Study (FHS; n = 1177) and validated in the Jackson Heart Study (JHS; n = 772) and Multi-Ethnic Study of Atherosclerosis (MESA; n = 1367). Proteins associated with incident hypertension were tested for putative causal links in approximately 700 000 individuals using cis-protein quantitative loci mendelian randomization (cis-MR). Data were analyzed from January 2023 to January 2024.ExposuresPlasma proteins.Main Outcomes and MeasuresEBP was defined as the BP response during a fixed workload (50 W) on a cycle ergometer. Hypertension was defined as BP ≥140/90 mm Hg or taking antihypertensive medication.ResultsAmong the 681 participants in the HERITAGE Family Study, the mean (SD) age was 34 (13) years; 366 participants (54%) were female; 238 (35%) were self-reported Black and 443 (65%) were self-reported White. Proteomic profiling of EBP revealed 34 proteins that would not have otherwise been identified through profiling of resting BP alone. Transforming growth factor β receptor 3 (TGFBR3) and prostaglandin D2 synthase (PTGDS) had the strongest association with exercise systolic BP (SBP) and diastolic BP (DBP), respectively (TGFBR3: exercise SBP, β estimate, −3.39; 95% CI, −4.79 to −2.00; P = 2.33 × 10−6; PTGDS: exercise DBP β estimate, −2.50; 95% CI, −3.29 to −1.70; P = 1.18 × 10−9). In fully adjusted models, TGFBR3 was inversely associated with incident hypertension in FHS, JHS, and MESA (hazard ratio [HR]: FHS, 0.86; 95% CI, 0.75-0.97; P = .01; JHS, 0.87; 95% CI, 0.77-0.97; P = .02; MESA, 0.84; 95% CI, 0.71-0.98; P = .03; pooled cohort, 0.86; 95% CI, 0.79-0.92; P = 6 × 10−5). Using cis-MR, genetically predicted levels of TGFBR3 were associated with SBP, hypertension, and CVD events (SBP: β, −0.38; 95% CI, −0.64 to −0.11; P = .006; hypertension: odds ratio [OR], 0.99; 95% CI, 0.98-0.99; P &lt; .001; heart failure with hypertension: OR, 0.86; 95% CI, 0.77-0.97; P = .01; CVD: OR, 0.84; 95% CI, 0.77-0.92; P = 8 × 10−5; cerebrovascular events: OR, 0.77; 95% CI, 0.70-0.85; P = 5 × 10−7).Conclusions and RelevancePlasma proteomic profiling of EBP identified a novel protein, TGFBR3, which may protect against elevated BP and long-term CVD outcomes.

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

Cited by 196 publications

References 87 publications

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

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

Multi-ancestry Mendelian randomization of omics traits revealing drug targets of COVID-19 severity

Plasma Proteomics of Exercise Blood Pressure and Incident Hypertension

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