| Title: | Rare and common genetic determinants of metabolic individuality and their effects on human health |
| Journal: | Nature Medicine |
| Published: | 10 Nov 2022 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/36357675/ |
| DOI: | https://doi.org/10.1038/s41591-022-02046-0 |
| URL: | https://www.nature.com/articles/s41591-022-02046-0.pdf |
Publication 10679
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Abstract
Garrod's concept of 'chemical individuality' has contributed to comprehension of the molecular origins of human diseases. Untargeted high-throughput metabolomic technologies provide an in-depth snapshot of human metabolism at scale. We studied the genetic architecture of the human plasma metabolome using 913 metabolites assayed in 19,994 individuals and identified 2,599 variant-metabolite associations (P < 1.25 × 10−11) within 330 genomic regions, with rare variants (minor allele frequency ≤ 1%) explaining 9.4% of associations. Jointly modeling metabolites in each region, we identified 423 regional, co-regulated, variant-metabolite clusters called genetically influenced metabotypes. We assigned causal genes for 62.4% of these genetically influenced metabotypes, providing new insights into fundamental metabolite physiology and clinical relevance, including metabolite-guided discovery of potential adverse drug effects (DPYD and SRD5A2). We show strong enrichment of inborn errors of metabolism-causing genes, with examples of metabolite associations and clinical phenotypes of non-pathogenic variant carriers matching characteristics of the inborn errors of metabolism. Systematic, phenotypic follow-up of metabolite-specific genetic scores revealed multiple potential etiological relationships.</p>
36 Authors
- Praveen Surendran
- Isobel D. Stewart
- Victoria P. W. Au Yeung
- Maik Pietzner
- Johannes Raffler
- Maria A. Wörheide
- Chen Li
- Rebecca F. Smith
- Laura B. L. Wittemans
- Lorenzo Bomba
- Cristina Menni
- Jonas Zierer
- Niccolò Rossi
- Patricia A. Sheridan
- Nicholas A. Watkins
- Massimo Mangino
- Pirro G. Hysi
- Emanuele Di Angelantonio
- Mario Falchi
- Tim D. Spector
- Nicole Soranzo
- Gregory A. Michelotti
- Wiebke Arlt
- Luca A. Lotta
- Spiros Denaxas
- Harry Hemingway
- Eric R. Gamazon
- Joanna M. M. Howson
- Angela M. Wood
- John Danesh
- Nicholas J. Wareham
- Gabi Kastenmüller
- Eric B. Fauman
- Karsten Suhre
- Adam S. Butterworth
- Claudia Langenberg
1 Application
| Application ID | Title |
|---|---|
| 44448 | The genetic and environmental determinants of cardiometabolic and related disorders. |
Enabling scientific discoveries that improve human health