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; Emanuele Di Angelantonio; David J Roberts; Willem H Ouwehand; INTERVAL study; Ian Dunham; Adam S Butterworth; Nicole Soranzo

doi:10.1016/j.ajhg.2022.04.009

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

Am J Hum Genet. 2022 Jun 2;109(6):1038-1054. doi: 10.1016/j.ajhg.2022.04.009. Epub 2022 May 13.

Authors

Lorenzo Bomba¹, Klaudia Walter², Qi Guo³, Praveen Surendran⁴, Kousik Kundu⁵, Suraj Nongmaithem², Mohd Anisul Karim¹, Isobel D Stewart⁶, Claudia Langenberg⁷, John Danesh⁸, Emanuele Di Angelantonio⁹, David J Roberts¹⁰, Willem H Ouwehand⁵; INTERVAL study; Ian Dunham¹¹, Adam S Butterworth¹², Nicole Soranzo¹³

Affiliations

¹ Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK; Open Targets, Wellcome Genome Campus, Hinxton CB10 1SD, UK.
² Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK.
³ British 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.
⁴ British 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.
⁵ Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Puddicombe Way, Cambridge CB2 0AW, UK.
⁶ MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0SL, UK.
⁷ MRC 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.
⁸ Wellcome 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.
⁹ 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; Human Technopole, Palazzo Italia, Viale Rita Levi-Montalcini 1, 20157 Milan, Italy.
¹⁰ National 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.
¹¹ Wellcome 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.
¹² 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.
¹³ Wellcome 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.

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.

Keywords: WES; WGS; drug targets; endophenotypes; loss-of-function; metabolomics; metabolon; proteomics; rare genetic variant; sequencing.

MeSH terms

Exome Sequencing / methods
Exome* / genetics
Gene Frequency / genetics
Humans
Prospective Studies
Whole Genome Sequencing

Abstract

MeSH terms

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