Phenome-wide Mendelian randomization mapping the influence of the plasma proteome on complex diseases.

Published on Sep 7, 2020in Nature Genetics38.33
路 DOI :10.1038/S41588-020-0682-6
Jie Zheng21
Estimated H-index: 21
(UoB: University of Bristol),
Valeriia Haberland8
Estimated H-index: 8
(UoB: University of Bristol)
+ 31 AuthorsTom R. Gaunt70
Estimated H-index: 70
(UoB: University of Bristol)
The human proteome is a major source of therapeutic targets. Recent genetic association analyses of the plasma proteome enable systematic evaluation of the causal consequences of variation in plasma protein levels. Here we estimated the effects of 1,002 proteins on 225 phenotypes using two-sample Mendelian randomization (MR) and colocalization. Of 413 associations supported by evidence from MR, 130 (31.5%) were not supported by results of colocalization analyses, suggesting that genetic confounding due to linkage disequilibrium is widespread in naive phenome-wide association studies of proteins. Combining MR and colocalization evidence in cis-only analyses, we identified 111 putatively causal effects between 65 proteins and 52 disease-related phenotypes ( Evaluation of data from historic drug development programs showed that target-indication pairs with MR and colocalization support were more likely to be approved, evidencing the value of this approach in identifying and prioritizing potential therapeutic targets. Mendelian randomization (MR) and colocalization analyses are used to estimate causal effects of 1,002 plasma proteins on 225 phenotypes. Evidence from drug developmental programs shows that target-indication pairs with MR and colocalization support were more likely to be approved, highlighting the value of this approach for prioritizing therapeutic targets.
馃摉 Papers frequently viewed together
34 Authors (Jie Zheng, ..., Shan Luo)
20 Authors (Ryan Langdon)
#1Qingyuan ZhaoH-Index: 14
#2Jingshu WangH-Index: 6
Last. Dylan S. SmallH-Index: 50
view all 5 authors...
Mendelian randomization (MR) is a method of exploiting genetic variation to unbiasedly estimate a causal effect in presence of unmeasured confounding. MR is being widely used in epidemiology and other related areas of population science. In this paper, we study statistical inference in the increasingly popular two-sample summary-data MR design. We show a linear model for the observed associations approximately holds in a wide variety of settings when all the genetic variants satisfy the exclusio...
#1David Stacey (University of Cambridge)H-Index: 15
#2Lingyan Chen (University of Cambridge)H-Index: 1
Last. Dirk S. Paul (University of Cambridge)H-Index: 28
view all 25 authors...
Genome-wide association studies have identified many individual genetic loci associated with multiple complex traits and common diseases. There are, however, few examples where the molecular basis of such pleiotropy has been elucidated. To address this challenge, we describe an integrative approach, focusing on the p.Ser219Gly (rs867186 A>G) variant in the PROCR gene (encoding the endothelial protein C receptor, EPCR), which has been associated with lower coronary artery disease (CAD) risk but h...
#1Ying Wu (UNC: University of North Carolina at Chapel Hill)H-Index: 45
#2K. Alaine Broadaway (UNC: University of North Carolina at Chapel Hill)H-Index: 2
Last. Adam E. Locke (WashU: Washington University in St. Louis)H-Index: 30
view all 21 authors...
Integration of genome-wide association study (GWAS) signals with expression quantitative trait loci (eQTL) studies enables identification of candidate genes. However, evaluating whether nearby signals may share causal variants, termed colocalization, is affected by the presence of allelic heterogeneity, different variants at the same locus impacting the same phenotype. We previously identified eQTL in subcutaneous adipose tissue from 770 participants in the Metabolic Syndrome in Men (METSIM) stu...
#1Michael Chong (Population Health Research Institute)H-Index: 16
#2Jennifer Sjaarda (Population Health Research Institute)H-Index: 7
Last. Guillaume Par茅H-Index: 73
view all 8 authors...
Background: Novel, effective, and safe drugs are warranted for treatment of ischemic stroke. Circulating protein biomarkers with causal genetic evidence represent promising drug targets, but no sys...
#1Michael Wainberg (Stanford University)H-Index: 15
#2Nasa Sinnott-Armstrong (Stanford University)H-Index: 16
Last. Anshul Kundaje (Stanford University)H-Index: 58
view all 15 authors...
Transcriptome-wide association studies (TWAS) integrate genome-wide association studies (GWAS) and gene expression datasets to identify gene鈥搕rait associations. In this Perspective, we explore properties of TWAS as a potential approach to prioritize causal genes at GWAS loci, by using simulations and case studies of literature-curated candidate causal genes for schizophrenia, low-density-lipoprotein cholesterol and Crohn鈥檚 disease. We explore risk loci where TWAS accurately prioritizes the likel...
#1Terry Solomon (UCSD: University of California, San Diego)H-Index: 7
#2John D. Lapek (UM: University of Montana)H-Index: 15
Last. John-Bjarne Hansen (UNN: University Hospital of North Norway)H-Index: 149
view all 12 authors...
Background: Identifying genetic variation associated with plasma protein levels, and the mechanisms by which they act, could provide insight into alterable processes involved in regulation of prote...
#1Paul M. Ridker (Brigham and Women's Hospital)H-Index: 255
#2Peter Libby (Brigham and Women's Hospital)H-Index: 240
Last. Robert J. Glynn (Brigham and Women's Hospital)H-Index: 167
view all 10 authors...
Aims: Canakinumab, a monoclonal antibody targeting interleukin (IL)-1尾, reduces rates of recurrent cardiovascular events without lowering lipids. It is uncertain, however, to what extent these beneficial cardiovascular outcomes are mediated through interleukin-6 (IL-6) signalling, an issue with substantial pathophysiologic consequences and therapeutic implications. Methods and results: A total of 4833 stable atherosclerosis patients in the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study ...
#3Jie Zheng (UoB: University of Bristol)H-Index: 4
We have undertaken a systematic Mendelian randomization (MR) study using methylation quantitative trait loci (meQTL) as genetic instruments to assess the relationship between genetic variation, DNA methylation and 139 complex traits. Using two-sample MR, we identified 1148 associations across 61 traits where genetic variants were associated with both proximal DNA methylation (i.e. cis-meQTL) and complex trait variation (P鈥<鈥1.39 脳 10-08). Joint likelihood mapping provided evidence that the genet...
#1Valur Emilsson (University of Iceland)H-Index: 52
#2Marjan IlkovH-Index: 10
Last. Vilmundur Gudnason (University of Iceland)H-Index: 159
view all 28 authors...
Proteins circulating in the blood are critical for age-related disease processes; however, the serum proteome has remained largely unexplored. To this end, 4137 proteins covering most predicted extracellular proteins were measured in the serum of 5457 Icelanders over 65 years of age. Pairwise correlation between proteins as they varied across individuals revealed 27 different network modules of serum proteins, many of which were associated with cardiovascular and metabolic disease states, as wel...
#1Chen Yao (NIH: National Institutes of Health)H-Index: 23
#2George Chen (NIH: National Institutes of Health)H-Index: 10
Last. Hongsheng Wu (Wentworth Institute of Technology)H-Index: 6
view all 24 authors...
Identifying genetic variants associated with circulating protein concentrations (protein quantitative聽trait loci; pQTLs) and integrating them with variants from genome-wide association studies (GWAS) may illuminate the proteome鈥檚 causal role in disease and bridge a knowledge gap regarding SNP-disease associations. We provide the results of GWAS of 71 high-value cardiovascular disease proteins in 6861 Framingham Heart Study participants and independent external replication. We report the mapping ...
Cited By61
#1Bjarni V. Halldorsson (Amgen)H-Index: 51
#2Hannes P. Eggertsson (Amgen)H-Index: 12
Last. Kari Stefansson (Amgen)H-Index: 214
view all 48 authors...
We describe the analysis of whole genome sequencing (WGS) of 150,119 individuals from the UK biobank (UKB). This yielded a set of high quality variants, including 585,040,410 SNPs, representing 7.0% of all possible human SNPs, and 58,707,036 indels. The large set of variants allows us to characterize selection based on sequence variation within a population through a Depletion Rank (DR) score for windows along the genome. DR analysis shows that coding exons represent a small fraction of regions ...
#1Lingyan Chen (BHF: British Heart Foundation)
#2James E. Peters (Imperial College London)H-Index: 15
Last. Joanna M. M. Howson (BHF: British Heart Foundation)H-Index: 63
view all 19 authors...
Proteins are the effector molecules of biology and are the target of most drugs. To identify proteins and related pathways that may play a causal role in stroke pathogenesis, we used Mendelian randomisation (MR). We tested potential causal effects of 308 plasma proteins (measured in 4,994 blood donors from the INTERVAL study) on stroke outcomes (derived from the MEGASTROKE GWAS) in a two-sample MR framework and assessed whether these associations could be mediated by cardiovascular risk factors....
#1Scott C. RitchieH-Index: 14
#2Samuel A. LambertH-Index: 11
Last. Yingying Liu (Baker IDI Heart and Diabetes Institute)H-Index: 6
view all 25 authors...
Cardiometabolic diseases are frequently polygenic in architecture, comprising a large number of risk alleles with small effects spread across the genome1鈥3. Polygenic scores (PGS) aggregate these into a metric representing an individual鈥檚 genetic predisposition to disease. PGS have shown promise for early risk prediction4鈥7 and there is an open question as to whether PGS can also be used to understand disease biology8. Here, we demonstrate that cardiometabolic disease PGS can be used to elucidat...
Complex traits are characterized by multiple genes and variants acting simultaneously on a phenotype. However, studying the contribution of individual pairs of genes to complex traits has been challenging since human genetics necessitates very large population sizes, while findings from model systems do not always translate to humans. Here, we combine genetics with combinatorial RNAi (coRNAi) to systematically test for pairwise additive effects (AEs) and genetic interactions (GIs) between 30 lip...
#1Lu Wang (UM: University of Michigan)
#2Boran Gao (UM: University of Michigan)H-Index: 1
Last. Xiang Zhou (UM: University of Michigan)H-Index: 31
view all 5 authors...
Mendelian randomization (MR) is a common analytic tool for exploring the causal relationship among complex traits. Existing MR methods require selecting a small set of single nucleotide polymorphisms (SNPs) to serve as instrument variables. However, selecting a small set of SNPs may not be ideal, as most complex traits have a polygenic or omnigenic architecture and are each influenced by thousands of SNPs. Here, motivated by the recent omnigenic hypothesis, we present an MR method that uses all ...
#8Higgins Jp (UoB: University of Bristol)H-Index: 4
Mendelian randomisation (MR) studies allow a better understanding of the causal effects of modifiable exposures on health outcomes, but the published evidence is often hampered by inadequate reporting. Reporting guidelines help authors effectively communicate all critical information about what was done and what was found. STROBE-MR (strengthening the reporting of observational studies in epidemiology using mendelian randomisation) assists authors in reporting their MR research clearly and trans...
#1Maria Gordillo-Maranon (UCL: University College London)H-Index: 3
#2Magdalena Zwierzyna (BHF: British Heart Foundation)H-Index: 6
Last. Goya Wannamethee (UCL: University College London)H-Index: 40
view all 21 authors...
Drug target Mendelian randomization (MR) studies use DNA sequence variants in or near a gene encoding a drug target, that alter the target鈥檚 expression or function, as a tool to anticipate the effect of drug action on the same target. Here we apply MR to prioritize drug targets for their causal relevance for coronary heart disease (CHD). The targets are further prioritized using independent replication, co-localization, protein expression profiles and data from the British National Formulary and...
#1Maik Pietzner (University of Cambridge)H-Index: 21
#2Eleanor Wheeler (University of Cambridge)H-Index: 18
Last. Nicola D. Kerrison (University of Cambridge)H-Index: 18
view all 21 authors...
The Fenland Study (10.22025/2017.10.101.00001) is funded by the Medical Research Council (MC_UU_12015/1). We further acknowledge support for genomics from the Medical Research Council (MC_PC_13046). ERG is supported by the National Institutes of Health (NIH) Awards R35HG010718, R01HG011138, R01GM140287, and NIH/NIA AG068026. MAW, MA, and GK are supported by grants from the National Institute on Aging (NIA): null U01 AG061359, RF1 AG057452, and RF1 AG059093). JCZ is supported by a 4-year Wellcome...
#1Annie H. Ren (Lunenfeld-Tanenbaum Research Institute)H-Index: 2
#2Eleftherios P. Diamandis (Lunenfeld-Tanenbaum Research Institute)H-Index: 132
Last. Vathany Kulasingam (U of T: University of Toronto)H-Index: 25
view all 3 authors...
Abstract null null Probing the human proteome in tissues and biofluids such as plasma is attractive for biomarker and drug target discovery. Recent breakthroughs in multiplex, antibody-based, proteomics technologies now enable the simultaneous quantification of thousands of proteins at as low as sub fg/ml concentrations with remarkable dynamic ranges of up to 10-log. We herein provide a comprehensive guide to the methodologies, performance, technical comparisons, advantages, and disadvantages of...
#1Jie Zheng (UoB: University of Bristol)H-Index: 21
#2Haotian Tang (UoB: University of Bristol)
Last. George Davey Smith (UoB: University of Bristol)H-Index: 246
view all 11 authors...
Mendelian randomization (MR) studies carried out among patients with a particular health condition should establish the genetic instrument influences the exposure in that subgroup, however this is normally investigated in the general population. Here, we investigated whether the genetic associations of four cis-acting C-reactive protein (CRP) variants differed between participants with and without three cardiometabolic conditions: obesity, type 2 diabetes, and cardiovascular disease. Association...
This website uses cookies.
We use cookies to improve your online experience. By continuing to use our website we assume you agree to the placement of these cookies.
To learn more, you can find in our Privacy Policy.