Journal article
FNIP1 variants associated with favorable metabolism in 1 million humans
- Abstract:
- Altered energy metabolism is a shared driver of cardiometabolic disease, the leading cause of death globally. Energy metabolism varies between individuals and is partly heritable. To investigate its genetic basis, here we perform exome-sequencing in 1,032,116 people from America, Europe and Asia and estimate associations of rare protein-coding variants with the triglyceride-to-high-density-lipoprotein cholesterol (TG-HDL) ratio – an energy state biomarker that we associate with diverse cardiometabolic risk factors and diseases. We identify 59 independent genes (P<1.04×10⁻⁷), enriched for liver- and adipose-expressed master regulators of energy balance, storage and metabolism, with 23 (39%) encoding approved or clinical-stage drug targets. Ultra-rare protein-truncating variants in FNIP1 (allele frequency, 0.01%), encoding a suppressor of energy expenditure and mitochondrial metabolism, associate with lower TG-HDL ratio, lower liver fat, lower glycemia, favorable fat distribution and ~60% lower odds of cardiometabolic disease. FNIP1 knockdown in primary human hepatocytes induces lipid breakdown and lysosomal gene expression, while combined hepatic knockdown of Fnip1 with its paralog Fnip2 or knockdown of its interactor Flcn protect from weight gain, reduce liver fat and enhance insulin sensitivity in high-fatdiet mice. Our study implicates the FNIP1 pathway in human energy metabolism and highlights its inhibition as a potential therapeutic strategy in cardiometabolic disease.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 45.2MB, Terms of use)
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- Publisher copy:
- 10.1038/s41586-026-10864-2
Authors
+ British Heart Foundation
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- Funder identifier:
- https://ror.org/02wdwnk04
- Grant:
- CH/12/2/29428
- Grant:
- RG/18/13/33946
+ Medical Research Council
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- Funder identifier:
- https://ror.org/03x94j517
- Grant:
- MC_UU_00017/2
- Grant:
- MR/Z504543/1
- Grant:
- MR/P02811X/1
+ National Institutes of Health
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- Funder identifier:
- https://ror.org/01cwqze88
- Grant:
- UL1TR001878
+ NIHR Cambridge Biomedical Research Centre
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- Funder identifier:
- https://ror.org/05m8dr349
- Grant:
- BRC-121520014
+ National Institute for Health and Care Research
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- Funder identifier:
- https://ror.org/0187kwz08
- Grant:
- NIHR203312
- Publisher:
- Springer Nature
- Journal:
- Nature More from this journal
- Volume:
- 657
- Issue:
- 8132
- Pages:
- 703–712
- Publication date:
- 2026-08-05
- Acceptance date:
- 2026-06-30
- DOI:
- EISSN:
-
1476-4687
- ISSN:
-
0028-0836
- Language:
-
English
- Pubs id:
-
2439932
- Local pid:
-
pubs:2439932
- Deposit date:
-
2026-06-30
- ARK identifier:
Terms of use
- Copyright holder:
- Hindy et al
- Copyright date:
- 2026
- Rights statement:
- © The Author(s) 2026. This article is licensed under a Creative Commons AttributionNonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, 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 you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. 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-nc-nd/4.0/.
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