| Title: | Analysis of whole genome sequencing and plasma metabolomics unveil genetic determinants and clinical implications for human health |
| Journal: | Nature Communications |
| Published: | 22 Jun 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42331824/ |
| DOI: | https://doi.org/10.1038/s41467-026-74781-8 |
Publication 20579
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Abstract
Blood metabolites are critical biomarkers linking genetic variation to diverse health outcomes, exhibiting significant variability across individuals. Here, we analyze and integrate whole-genome sequencing with plasma metabolomics to investigate the genetic architecture of 313 metabolic biomarkers in up to 199,138 UK Biobank participants. Through single-variant analyses, we identify 36,105 independent signals, with 22.20% being novel. Furthermore, we pinpoint 12,361 putative causal variant-trait associations, demonstrating enhanced causal signal discovery and improved fine-mapping resolution compared with imputed array-based approaches. Rare-variant aggregate testing reveals 1,527 conditionally independent protein-coding gene-trait pairs, with 32.9% being unique to non-coding regions. We estimate the heritability at a median of h2 = 0.31, nearly tripling the heritability estimates obtained from array-based approaches. Integrating our findings with disease genetics reveals 245 potential causal associations, such as that between omega-3 fatty acids and cholelithiasis risk. Prioritizing proteins with concordant effects on metabolites and clinical outcomes revealed 410 potential targets, offering opportunities for therapeutic strategies and drug repurposing. Our open-access resource (https://metabolome-whole-genome-landscape.com/) provides a foundation for future research into metabolic pathways, disease mechanisms, and therapeutic development.</p>
16 Authors
- Yi-Xuan Wang
- Yi-Xuan Qiang
- Yi-Jun Ge
- Yue-Ting Deng
- Bang-Sheng Wu
- Liu Yang
- Yi-Lin Chen
- Xiao-Yu He
- Yu He
- Bing-Ran Yao
- Chen-Jie Fei
- Rui-Ying Yin
- Jia You
- Jian-Feng Feng
- Wei Cheng
- Jin-Tai Yu
Enabling scientific discoveries that improve human health