Genome-wide characterization of circulating metabolic biomarkers

Minna K Karjalainen; Ayse Demirkan; Savita Karthikeyan; Clare Oliver-Williams; Eeva Sliz; Elias Allara; Wing Tung Fung; Praveen Surendran; Weihua Zhang; Pekka Jousilahti; Kati Kristiansson; Veikko Salomaa; Matt Goodwin; David A Hughes; Michael Boehnke; Lilian Fernandes Silva; Xianyong Yin; Anubha Mahajan; Matt J Neville; Natalie R van Zuydam; Ruifang Li-Gao; Renée de Mutsert; Dennis O Mook-Kanamori; Jun Liu; Raymond Noordam; Stella Trompet; Zhengming Chen; Christiana Kartsonaki; Liming Li; Kuang Lin; Fiona A Hagenbeek; Jouke Jan Hottenga; René Pool; M Arfan Ikram; Joyce van Meurs; Toomas Haller; Yuri Milaneschi; Mika Kähönen; Pashupati P Mishra; Peter K Joshi; Erin Macdonald-Dunlop; Massimo Mangino; Jonas Zierer; Ilhan E Acar; Carel B Hoyng; Yara T. E Lechanteur; Lude Franke; Alexander Kurilshikov; Alexandra Zhernakova; Marian Beekman; Erik B van den Akker; Ivana Kolcic; Ozren Polasek; Igor Rudan; Christian Gieger; Melanie Waldenberger; Folkert W Asselbergs; Caroline Hayward; Jingyuan Fu; Anneke I den Hollander; Cristina Menni; Tim D Spector; James F Wilson; Terho Lehtimäki; Olli T Raitakari; Brenda W. J. H Penninx; Tonu Esko; Robin G Walters; J. Wouter Jukema; Naveed Sattar; Mohsen Ghanbari; Ko Willems van Dijk; Fredrik Karpe; Mark I McCarthy; Markku Laakso; Marjo-Riitta Järvelin; Nicholas J Timpson; Markus Perola; Jaspal S Kooner; John C Chambers; Cornelia van Duijn; P. Eline Slagboom; Dorret I Boomsma; John Danesh; Mika Ala-Korpela; Adam S Butterworth; Johannes Kettunen

doi:10.1038/s41586-024-07148-y

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Genome-wide characterization of circulating metabolic biomarkers

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Genome-wide characterization of circulating metabolic biomarkers

Minna K Karjalainen, Ayse Demirkan, Savita Karthikeyan, Clare Oliver-Williams, Eeva Sliz, Elias Allara, Wing Tung Fung, Praveen Surendran, Weihua Zhang, Pekka Jousilahti, …

Nature, Vol.628(8006), pp.130-138

06/03/2024

DOI: https://doi.org/10.1038/s41586-024-07148-y

PMID: 38448586

Abstract

Acetone - blood

Acetone - metabolism

Biomarkers - blood

Biomarkers - metabolism

Cholestasis, Intrahepatic - blood

Cholestasis, Intrahepatic - genetics

Cholestasis, Intrahepatic - metabolism

Cohort Studies

Female

Genome-Wide Association Study - methods

Humans

Hypertension - blood

Hypertension - genetics

Hypertension - metabolism

Lipoproteins - genetics

Lipoproteins - metabolism

Magnetic Resonance Spectroscopy

Mendelian Randomization Analysis

Metabolic Networks and Pathways - genetics

Metabolomics

Polymorphism, Single Nucleotide - genetics

Pregnancy Complications - blood

Pregnancy Complications - genetics

Pregnancy Complications - metabolism

Phenotype

Pregnancy

Genome-wide association analyses using high-throughput metabolomics platforms have led to novel insights into the biology of human metabolism . This detailed knowledge of the genetic determinants of systemic metabolism has been pivotal for uncovering how genetic pathways influence biological mechanisms and complex diseases . Here we present a genome-wide association study for 233 circulating metabolic traits quantified by nuclear magnetic resonance spectroscopy in up to 136,016 participants from 33 cohorts. We identify more than 400 independent loci and assign probable causal genes at two-thirds of these using manual curation of plausible biological candidates. We highlight the importance of sample and participant characteristics that can have significant effects on genetic associations. We use detailed metabolic profiling of lipoprotein- and lipid-associated variants to better characterize how known lipid loci and novel loci affect lipoprotein metabolism at a granular level. We demonstrate the translational utility of comprehensively phenotyped molecular data, characterizing the metabolic associations of intrahepatic cholestasis of pregnancy. Finally, we observe substantial genetic pleiotropy for multiple metabolic pathways and illustrate the importance of careful instrument selection in Mendelian randomization analysis, revealing a putative causal relationship between acetone and hypertension. Our publicly available results provide a foundational resource for the community to examine the role of metabolism across diverse diseases.

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Title: Genome-wide characterization of circulating metabolic biomarkers
Creators: Minna K Karjalainen (Corresponding Author) - University of Oulu
Ayse Demirkan - University of Surrey, Institute for Sustainability
Savita Karthikeyan - British Heart Foundation
Clare Oliver-Williams - British Heart Foundation
Eeva Sliz - University of Oulu
Elias Allara - National Institute for Health Research
Wing Tung Fung - University of Cambridge
Praveen Surendran - University of Cambridge
Weihua Zhang - Imperial College London
Pekka Jousilahti - Finnish Institute for Health and Welfare
Kati Kristiansson - Finnish Institute for Health and Welfare
Veikko Salomaa - University of Oxford
Matt Goodwin - MRC Epidemiology Unit
David A Hughes - University of Bristol
Michael Boehnke - Biostat
Lilian Fernandes Silva - University of Eastern Finland
Xianyong Yin - University of Michigan–Ann Arbor
Anubha Mahajan - University of Oxford
Matt J Neville - Oxford Centre for Diabetes, Endocrinology and Metabolism
Natalie R van Zuydam - University of Oxford
Ruifang Li-Gao - Leiden University Medical Center
Renée de Mutsert - Leiden University Medical Center
Dennis O Mook-Kanamori - Leiden University
Jun Liu - Vrije Universiteit Amsterdam
Raymond Noordam - Leiden University Medical Center
Stella Trompet - University of Edinburgh
Zhengming Chen - University of Oxford
Christiana Kartsonaki - University of Cambridge
Liming Li - Peking University
Kuang Lin - University of Oxford
Fiona A Hagenbeek - Vrije Universiteit Amsterdam
Jouke Jan Hottenga - University of Amsterdam
René Pool - Vrije Universiteit Amsterdam
M Arfan Ikram - Biobanking and BioMolecular resources Research Infrastructure The Netherlands
Joyce van Meurs
Toomas Haller - University of Tartu
Yuri Milaneschi - Vrije Universiteit Amsterdam
Mika Kähönen - Turku University Hospital
Pashupati P Mishra
Peter K Joshi - University of Edinburgh
Erin Macdonald-Dunlop
Massimo Mangino - Thomas Foundation
Jonas Zierer - Helmholtz Zentrum München
Ilhan E Acar
Carel B Hoyng - University Hospital and Clinics
Yara T. E Lechanteur
Lude Franke - University of Groningen
Alexander Kurilshikov - University of Groningen
Alexandra Zhernakova - University Medical Center Groningen
Marian Beekman - Leiden University Medical Center
Erik B van den Akker - Leiden University Medical Center
Ivana Kolcic - University of Split
Ozren Polasek - Gen-info
Igor Rudan - University of Edinburgh
Christian Gieger - Uppsala University
Melanie Waldenberger - Helmholtz Zentrum München
Folkert W Asselbergs - Erasmus MC
Caroline Hayward - MRC Institute of Genetics and Molecular Medicine
Jingyuan Fu - University Medical Center Groningen
Anneke I den Hollander - Radboud University Nijmegen
Cristina Menni - King's College London
Tim D Spector - National Institute for Health Research
James F Wilson - MRC Institute of Genetics and Molecular Medicine
Terho Lehtimäki - Tampere University Hospital
Olli T Raitakari - University of Turku
Brenda W. J. H Penninx - Amsterdam UMC Location VUmc
Tonu Esko - University of Tartu
Robin G Walters - University of Oxford
J. Wouter Jukema - Leiden University Medical Center
Naveed Sattar - British Heart Foundation
Mohsen Ghanbari - Erasmus MC
Ko Willems van Dijk - Leiden University Medical Center
Fredrik Karpe - Oxford Centre for Diabetes, Endocrinology and Metabolism
Mark I McCarthy - University of Oxford
Markku Laakso - Kuopio University Hospital
Marjo-Riitta Järvelin - Georgia Institute of Technology
Nicholas J Timpson - Medical Research Council
Markus Perola - University of Helsinki
Jaspal S Kooner - Imperial College London
John C Chambers - Imperial College London
Cornelia van Duijn - Erasmus MC
P. Eline Slagboom - Leiden University Medical Center
Dorret I Boomsma - EMGO Institute for Health and Care Research
John Danesh - University of Cambridge
Mika Ala-Korpela - University of Oulu
Adam S Butterworth - University of Cambridge
Johannes Kettunen - University of Helsinki
Publication Details: Nature, Vol.628(8006), pp.130-138
Publisher: Nature Research
Number of pages: 21
Publication Date: 06/03/2024
Date accepted for publication: 01/02/2024
Grants: Wellcome Trust Investigator, 202802/Z/16/Z, Wellcome Trust (United Kingdom, London) - WT
MC_UU_00011/1, Medical Research Council (United Kingdom, London) - MRC
MC_UU_00011/6, Medical Research Council (United Kingdom, London) - MRC
WT 217065/Z/19/Z, Wellcome Trust (United Kingdom, London) - WT
BRC-1215-2001, University of Bristol (United Kingdom, Bristol)
C18281/A29019, Cancer Research UK (United Kingdom, London) - CRUK
Grant note: For full details of funding sources and those funded, please see here: http://static-content.springer.com/esm/art%3A10.1038%2Fs41586-024-07148-y/MediaObjects/41586_2024_7148_MOESM1_ESM.pdf
Identifiers: 99960266602346; WOS:001185076800020
Copyright: Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Academic Unit: Institute for Sustainability; School of Biosciences; Surrey Institute for People-Centred AI
Language: English
Resource Type: Journal article
Data Access Statement: Full GWAS summary statistics are publicly available through the NHGRI-EBI GWAS catalogue (GCST90301941–GCST90302173) and https://www.phpc.cam.ac.uk/ceu/lipids-and-metabolites/. Individual-level raw metabolic data from the INTERVAL study can be requested as instructed in https://www.phpc.cam.ac.uk/ceu/lipids-and-metabolites/. For access to individual-level genotype and phenotype data for the other studies included in this meta-analysis, please see Supplementary Table 1 for details of websites or references of the individual studies. The NMR metabolomics platform, including the proprietary analysis software, is protected by the intellectual property rights of Nightingale Health, therefore the NMR spectra are not in the possession of the authors and cannot be made publicly available. Source data are provided with this paper.

Genome-wide characterization of circulating metabolic biomarkers

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