Evidence map›Paper›PMID 35568032›Full record

ArticleAmerican journal of human genetics2022

Whole-exome sequencing identifies rare genetic variants associated with human plasma metabolites.

Lorenzo Bomba, Klaudia Walter, Qi Guo, Praveen Surendran, Kousik Kundu, Suraj Nongmaithem, Mohd Anisul Karim, Isobel D Stewart, Claudia Langenberg, John Danesh and 7 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in American journal of human genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.

0numbers the graph read from it
0cells of the map it votes in
32citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

32 citing papers in PubMed.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

17 authors.

Lorenzo BombaWellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK; Open Targets, Wellcome Genome Campus, Hinxton CB10 1SD, UK.
Klaudia WalterWellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK.
Qi GuoBritish Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK; National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge CB1 8RN, UK.
Praveen SurendranBritish Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Puddicombe Way, Cambridge CB2 0AW, UK.
Kousik KunduWellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Puddicombe Way, Cambridge CB2 0AW, UK.
Suraj NongmaithemWellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK.
Mohd Anisul KarimWellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK; Open Targets, Wellcome Genome Campus, Hinxton CB10 1SD, UK.
Isobel D StewartMRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0SL, UK.
Claudia LangenbergMRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0SL, UK; Computational Medicine, Berlin Institute of Health at Charité - Utniversitätsmedizin Berlin, Berlin 10117, Germany.
John DaneshWellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK; British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK; British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge CB2 0QQ, UK; National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge CB1 8RN, UK; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge CB10 1SA, UK.
Emanuele Di AngelantonioBritish Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK; British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge CB2 0QQ, UK; National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge CB1 8RN, UK; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge CB10 1SA, UK; Human Technopole, Palazzo Italia, Viale Rita Levi-Montalcini 1, 20157 Milan, Italy.
David J RobertsNational Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge CB1 8RN, UK; NHS Blood and Transplant-Oxford Centre, Level 2, John Radcliffe Hospital, Oxford OX3 9BQ, UK; Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9BQ, UK.
Willem H OuwehandWellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Puddicombe Way, Cambridge CB2 0AW, UK.
INTERVAL study
Ian DunhamWellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK; Open Targets, Wellcome Genome Campus, Hinxton CB10 1SD, UK; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton CB10 1SD, UK.
Adam S ButterworthBritish Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK; British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge CB2 0QQ, UK; National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge CB1 8RN, UK; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge CB10 1SA, UK.
Nicole SoranzoWellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK; Open Targets, Wellcome Genome Campus, Hinxton CB10 1SD, UK; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Puddicombe Way, Cambridge CB2 0AW, UK; British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge CB2 0QQ, UK; National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge CB1 8RN, UK; Human Technopole, Palazzo Italia, Viale Rita Levi-Montalcini 1, 20157 Milan, Italy. Electronic address: ns6@sanger.ac.uk.

Funding

British Heart Foundation CH/12/2/29428British Heart Foundation RG/13/13/30194British Heart Foundation RG/18/13/33946Medical Research Council MC_UU_00006/1
6 · The paper itself

Abstract

Metabolite levels measured in the human population are endophenotypes for biological processes. We combined sequencing data for 3,924 (whole-exome sequencing, WES, discovery) and 2,805 (whole-genome sequencing, WGS, replication) donors from a prospective cohort of blood donors in England. We used multiple approaches to select and aggregate rare genetic variants (minor allele frequency [MAF] < 0.1%) in protein-coding regions and tested their associations with 995 metabolites measured in plasma by using ultra-high-performance liquid chromatography-tandem mass spectrometry. We identified 40 novel associations implicating rare coding variants (27 genes and 38 metabolites), of which 28 (15 genes and 28 metabolites) were replicated. We developed algorithms to prioritize putative driver variants at each locus and used mediation and Mendelian randomization analyses to test directionality at associations of metabolite and protein levels at the ACY1 locus. Overall, 66% of reported associations implicate gene targets of approved drugs or bioactive drug-like compounds, contributing to drug targets' validating efforts.

Indexed as

ExomeExome SequencingGene FrequencyHumansProspective StudiesWhole Genome Sequencingdrug targetsendophenotypesloss-of-functionmetabolomicsmetabolonproteomicsrare genetic variantsequencingWESWGS

Identifiers

PMID35568032
PMCPMC9247822

What Socratic holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.