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Linking protein to phenotype with Mendelian Randomization detects 38 proteins with causal roles in human diseases and traits
- Source :
- PLoS Genetics, Vol 16, Iss 7, p e1008785 (2020), PLoS Genetics, Bretherick, A D, Canela-Xandri, O, Joshi, P K, Clark, D W, Rawlik, K, Boutin, T S, Zeng, Y, Amador, C, Navarro, P, Rudan, I, Wright, A F, Campbell, H, Vitart, V, Hayward, C, Wilson, J F, Tenesa, A, Ponting, C P, Baillie, J K & Haley, C 2020, ' Linking protein to phenotype with Mendelian Randomization detects 38 proteins with causal roles in human diseases and traits ', PLoS Genetics, vol. 16, no. 7, e1008785 . https://doi.org/10.1371/journal.pgen.1008785
- Publication Year :
- 2020
- Publisher :
- Public Library of Science (PLoS), 2020.
-
Abstract
- To efficiently transform genetic associations into drug targets requires evidence that a particular gene, and its encoded protein, contribute causally to a disease. To achieve this, we employ a three-step proteome-by-phenome Mendelian Randomization (MR) approach. In step one, 154 protein quantitative trait loci (pQTLs) were identified and independently replicated. From these pQTLs, 64 replicated locally-acting variants were used as instrumental variables for proteome-by-phenome MR across 846 traits (step two). When its assumptions are met, proteome-by-phenome MR, is equivalent to simultaneously running many randomized controlled trials. Step 2 yielded 38 proteins that significantly predicted variation in traits and diseases in 509 instances. Step 3 revealed that amongst the 271 instances from GeneAtlas (UK Biobank), 77 showed little evidence of pleiotropy (HEIDI), and 92 evidence of colocalization (eCAVIAR). Results were wide ranging: including, for example, new evidence for a causal role of tyrosine-protein phosphatase non-receptor type substrate 1 (SHPS1; SIRPA) in schizophrenia, and a new finding that intestinal fatty acid binding protein (FABP2) abundance contributes to the pathogenesis of cardiovascular disease. We also demonstrated confirmatory evidence for the causal role of four further proteins (FGF5, IL6R, LPL, LTA) in cardiovascular disease risk.<br />Author summary The targets of most medications prescribed today are proteins. For many common diseases our understanding of the underlying causes is often incomplete, and our ability to predict whether new drugs will be effective is remarkably poor. Attempts to use genetics to identify drug targets have an important limitation: standard study designs link disease risk to DNA but do not explain how the genotype leads to disease. In our study, we made robust statistical links between DNA variants and blood levels of 249 proteins, in two separate groups of Europeans. We then used this information to predict protein levels in large genetic studies. In many cases, this second step gives us evidence that high or low levels of a given protein play a role in causing a given disease. Among dozens of high-confidence links, we found new evidence for a causal role of a protein called SHPS1 in schizophrenia, and of another protein (FABP2) in heart disease. Our method takes advantage of information from large numbers of existing genetic studies to prioritize specific proteins as drug targets.
- Subjects :
- Male
Cancer Research
Proteome
Pulmonology
Genome-wide association study
Disease
QH426-470
Vascular Medicine
0302 clinical medicine
Mathematical and Statistical Techniques
Pleiotropy
Drug Discovery
Medicine and Health Sciences
Coronary Heart Disease
Receptors, Immunologic
Lymphotoxin-alpha
Genetics (clinical)
Genetics
0303 health sciences
Statistics
Genomics
Phenotype
Cardiovascular Diseases
Physical Sciences
Female
Research Article
Drug Research and Development
Fibroblast Growth Factor 5
Quantitative Trait Loci
Cardiology
Single-nucleotide polymorphism
Quantitative trait locus
Biology
Fatty Acid-Binding Proteins
Research and Analysis Methods
Instrumental Variable Analysis
03 medical and health sciences
Mendelian randomization
Mental Health and Psychiatry
Genome-Wide Association Studies
Humans
Allele
Statistical Methods
Molecular Biology
Ecology, Evolution, Behavior and Systematics
Genetic Association Studies
Alleles
030304 developmental biology
Pharmacology
Biology and Life Sciences
Computational Biology
Human Genetics
Mendelian Randomization Analysis
Genome Analysis
Antigens, Differentiation
Receptors, Interleukin-6
Asthma
Lipoprotein Lipase
Genetic Loci
Genetics of Disease
Schizophrenia
030217 neurology & neurosurgery
Mathematics
Subjects
Details
- Language :
- English
- ISSN :
- 15537404 and 15537390
- Volume :
- 16
- Issue :
- 7
- Database :
- OpenAIRE
- Journal :
- PLoS Genetics
- Accession number :
- edsair.doi.dedup.....5f99d4e21cf16b3686a729a22ff7ce3a