FNIP1 variants associated with favorable metabolism in 1 million humans

Hindy, G; Adam, RC; Sosina, O; Pryce, D; Blair, D; Herman, J; Lee, J; Dornbos, P; Mayerhofer, E; Gilly, A; Charleen, H; Geraghty, B; Landheer, K; Ganel, L; Baldassari, A; Zhang, C; Mintah, I; Sun, D; Coppola, A; Brown, K; Nguyen, T; Xia, X; Regeneron Genetics Center; GHS-RGC DiscovEHR Collaboration; Penn Medicine Biobank; Colorado Center for Personalized Medicine; Mayo Clinic-RGC Project Generation; Mexico City Prospective Study; Malmö Diet and Cancer Study; Indiana University School of Medicine (Indiana-CLDB); UCLA-RGC ATLAS Collaboration; Mount Sinai Million Health Discoveries Program; UTSW-Dallas Biobank; South Asia Biobank Study; Rader, DJ; Melander, O; Still, CD; Berumen, J; Kuri-Morales, P; Alegre-Díaz, J; Torres, J; Emberson, JR; Collins, R; Tapia-Conyer, R; Balasubramanian, S; Jones, MB; LeBlanc, MG; Murphy, AJ; Kyratsous, CA; Overton, JD; Reid, JG; Abecasis, GR; Marchini, J

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:: Accepted

Peer review status:: Peer reviewed

Actions

Email

Email this record

Send the bibliographic details of this record to your email address.

Your Email
Please enter the email address that the record information will be sent to.

-
Your message (optional)
Please add any additional information to be included within the email.
Share
Cite

Cite this record

APA Style

Hindy, G., Adam, R. C., Sosina, O., Pryce, D., Blair, D., Herman, J., Lee, J., Dornbos, P., Mayerhofer, E., Gilly, A., Charleen, H., Geraghty, B., Landheer, K., Ganel, L., Baldassari, A., Zhang, C., Mintah, I., Sun, D., Coppola, A., … Marchini, J. (2026). FNIP1 variants associated with favorable metabolism in 1 million humans. Nature.

MLA Style

Hindy, G, et al. “FNIP1 Variants Associated with Favorable Metabolism in 1 Million Humans.” Nature, 2026.

Chicago Style

Hindy, G, RC Adam, O Sosina, et al. 2026. “FNIP1 Variants Associated with Favorable Metabolism in 1 Million Humans.” Nature.
Print