@article {333879, title = {FNIP1 variants are associated with favourable metabolism in 1 million humans}, journal = {Nature}, year = {2026}, month = {2026/08/05}, abstract = {

Altered energy metabolism is a shared driver across cardiometabolic diseases\—the leading cause of death globally1. Energy metabolism varies between individuals and is partly heritable2,3,4,5,6,7,8,9. Here, to investigate the genetic basis of energy metabolism, we perform an\ exome-sequencing analysis of 1,032,116 people from America, Europe and Asia, and estimate associations between rare protein-coding variants and the ratio of triglyceride to high-density-lipoprotein cholesterol (TG:HDL)\—an energy-state biomarker that we associate with diverse cardiometabolic risk factors and diseases. We identify 59 independent genes (P\ \<\ 1.04\ \×\ 10\−7) that are enriched for liver- and adipose-expressed master regulators of energy balance, storage and metabolism; 23 (39\%) of these genes encode approved or clinical-stage drug targets. Ultra-rare protein-truncating variants in\ FNIP1\ (allele frequency, 0.01\%), which encodes a suppressor of energy expenditure and mitochondrial metabolism, are associated with a lower TG:HDL ratio, lower liver fat, lower glycaemia, favourable fat distribution and around 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 paralogue\ Fnip2\ or knockdown of its interactor\ Flcnprotect against weight gain, reduce liver fat and enhance insulin sensitivity in mice fed a high-fat diet. Our study implicates the FNIP1 pathway in human energy metabolism and highlights its inhibition as a potential therapeutic strategy in cardiometabolic disease.

}, isbn = {0028-08361476-4687}, doi = {http://dx.doi.org/10.1038/s41586-026-10864-2}, url = {https://www.nature.com/articles/s41586-026-10864-2}, author = {Hindy, George and Adam, Rene C. and Sosina, Olukayode and Pryce, Dwaine and Blair, David and Herman, Joseph and Lee, Joseph and Dornbos, Peter and Mayerhofer, Ernst and Gilly, Arthur and Hunt, Charleen and Geraghty, Benjamin and Landheer, Karl and Ganel, Liron and Baldassari, Antoine and Zhang, Chuanyi and Mintah, Ivory and Sun, Daphne and Coppola, Angel and Brown, Kyle and Nguyen, Tram and Xia, Xin and Deubler, Andrew and Ferrando, Adolfo and Coppola, Giovanni and Shuldiner, Alan and Siminovitch, Katherine and Portnoy, Jason and Mitnaul, Lyndon and Fenney, Alison and Ferreira, Manuel Allen Revez and Ghoussaini, Maya and Nafde, Mona and Salerno, William and Crane, Lourdes and Beechert, Christina and Fuller, Erin and Cremona, Laura M. and Kalyuskin, Eugene and Du, Hang and Forsythe, Caitlin and Gu, Zhenhua and Guevara, Kristy and Lattari, Michael and Lopez, Alexander and Manoochehri, Kia and Challa, Prathyusha and Pradhan, Manasi and Reynoso, Raymond and Schiavo, Ricardo and Padilla, Maria Sotiropoulos and Wang, Chenggu and Wolf, Sarah E. and Goyal, Manan and Mitra, George and Sreeram, Sanjay and Lanche, Rouel and Mahajan, Vrushali and Vasireddy, Sai Lakshmi and Eom, Gisu and Punuru, Krishna Pawan and Gokhale, Sujit and Sultan, Benjamin and Mule, Pooja and Sarwar, Mudasar and Aqeel, Muhammad and Bai, Xiaodong and Zhang, Lance and O{\textquoteright}Keeffe, Sean and Panea, Razvan and Edelstein, Evan and Rasool, Ayesha and Maxwell, Evan K. and Boutkov, Boris and Gorovits, Alexander and Guan, Ju and Habegger, Lukas and Hawes, Alicia and Krasheninina, Olga and Zarate, Samantha and Mansfield, Adam J. and Backman, Joshua and Burch, Kathy and Campos, Adrian and Gaynor, Sheila and Ghosh, Arkopravo and Martinez, Salvador Romero and Gillies, Christopher and Gurski, Lauren and Jorgenson, Eric and Joseph, Tyler and Kessler, Michael and Kosmicki, Jack and Nakka, Priyanka and Delaneau, Olivier and Marcketta, Anthony and Mbatchou, Joelle and Moscati, Arden and Pandit, Anita and Ross, Jonathan and Sidore, Carlo and Stahl, Eli and Thornton, Timothy and Vedantam, Sailaja and Wang, Rujin and Wu, Kuan-Han and Ye, Bin and Zhang, Blair and Ziyatdinov, Andrey and Zou, Yuxin and Zhang, Jingning and Watanabe, Kyoko and Tang, Mira and Wendt, Frank and Bao, Suying and Sun, Kathie and Yu, Sean and Zhang, Aaron and Corrigan, David and Shidhaye, Dhruv and Wang, Chen and Adhikari, Keyrun and Lachmann, Alexander and Weiner, Mark and Hobbs, Brian and Silver, Jon and Palmer, William and Guerreiro, Rita and Joshi, Amit and Graham, Sarah and Castineira, Erola Pairo and De, Tanima and Sun, Luanluan and Haas, Mary and Rodriguez-Flores, Juan and Riaz, Moeen and Kapoor, Manav and Tzoneva, Gannie and Jallow, Momodou W. and Alkelai, Anna and Ayer, Ariane and Rajagopal, Veera and Gelfman, Sahar and Kumar, Vijay and Otto, Jacqueline and Bras, Jose and Alvarez, Silvia and Brown, Jessie and Khiabanian, Hossein and Revez, Joana and Skead, Kimberly and Zavala, Valentina and Sul, Jae Soon and Chen, Lei and Choi, Sam and Damask, Amy and Lin, Nan and Paulding, Charles and Malhotra, Sameer and Rana, Nadia and Rico-Varela, Jennifer and Hernandez, Jaimee and Romero, Larizbeth and Paynter, Ashley and Schwartz, Randi and Hankins, Jody and Han, Anna and Hart, Samuel and Smith, Ryan and Perez-Beals, Ann and Solari, Gina and Rivera-Picart, Johannie and Pagan, Michelle and Siceron, Sunilbe and Buchanan, Adam and Carey, David J. and Martin, Christa L. and Meyer, Michelle and Retterer, Kyle and Rolston, David and Ritchie, Marylyn D. and Weaver, JoEllen and Naseer, Nawar and Sirugo, Giorgio and Poindexter, Afiya and Ko, Yi-An and Nerz, Kyle P. and Dever, Jenna and Harvey, Aidan and Linn, Sydney and Livingstone, Meghan and Vadivieso, Fred and DerOhannessian, Stephanie and Tran, Teo and Stephanowski, Julia and Santos, Salma and Haubein, Ned and Dunn, Joseph and Verma, Anurag and Kripke, Colleen Morse and Risman, Marjorie and Judy, Renae and Wollack, Colin and Verma, Shefali S. and Damrauer, Scott and Bradford, Yuki and Dudek, Scott and Drivas, Theodore and Anderson, Heather D. and Aquilante, Christina L. and Arbogast, Kelsey and Brooks, Ian M. and Burke, Elizabeth E. and Casteel, Emily M. and Cole, Joanne B. and Coughlin, Curtis R. and Crawford, Jacob and Crooks, Kristy and Culver, Erin and Fisher, Matthew J. and Frye, Teresa C. and George, Hunter and Gignoux, Chris R. and Gilliland, Elizabeth K. and Greene, Casey S. and Hearst, Emily and Hendricks, Audrey E. and Johnson, Randi K. and Jones, Shelby and Kao, Dave and Knortz, Gabrielle A. and Koffenberger, Danielle and Krishnamoorthy, Santhanagopalan and Ku, Lisa and Kudron, Elizabeth L. and Lacy, Rashawnda and Lange, Ethan M. and Lesny, Joe A. and Lin, Meng and Martin, James L. and Stewart, Adrian M. and Radwan, Alaa and Tanaka, Anna and Sanchez-Wild, Carolina and Swartz, Carolyn T. and Shalowitz, Elise L. and Todd, Emily B. and Sherif, Hoda and Pattee, Jack and Shortt, Jonathan A. and Trinkley, Katy E. and Wiley, Laura K. and Rasouli, Neda and Rafaels, Nick and McDaniel, Nicole L. and Pozdeyev, Nikita and Raghavan, Sridharan and Vohra, Vendant and Cerhan, James R. and Couch, Fergus J. and Olson, Janet E. and Larson, Nicholas B. and Fredericksen, Zachary S. and Cicek, Mine and Biernacka, Joanna M. and Karpyak, Victor M. and Vemuri, Prashanthi and Ramanan, Vijay K. and Frye, Mark A. and McLaughlin, Sarah A. and Ruddy, Kathryn J. and Bielinski, Suzette J. and Lieske, John C. and Hooten, W. Michael and Boardman, Lisa A. and Kennedy, Richard B. and Badley, Andrew D. and Dowdy, Sean C. and Bakkum-Gamez, Jamie N. and Glaser, Gretchen E. and Yang, Ping and Vachon, Celine M. and Dispenzieri, Angela and Antwi, Samuel O. and Oberg, Ann L. and Rabe, Kari G. and Kaufmann, Scott H. and Goode, Ellen L. and Cliby, William A. and Ahlskog, J. Eric and Bower, James H. and Harris, Peter C. and Pereira, Naveen L. and Ma, Daniel J. and Mutter, Robert W. and Eckel-Passow, Jeanette E. and Colborn, Lisa K. and Danielsen, Andrew J. and Harrington, Jonathan J. and Kushwaha, Jennifer M. and Chalasani, Naga P. and Schwantes-An, Tae-Hwi L. and Saykin, Andrew J. and Bui, Alex and Petruse, Antonia and Naeim, Arash and Denny, Chris and Lajonchere, Clara and Magyar, Clara and Geschwind, Dan and Ariannejad, Maryam and Boutros, Paul and Spellman, Paul and Dry, Sarah and Nelson, Stan and Duntugan, Albert and Pasaniuc, Bogdan and Tung, Paul and Chang, Tim and Berkovich, Yael and Jain, Ankur and Martinez, Danielle and Mohammed, Ghouse and Illiev, Lora and Broudy, Michael and Haas, Roni and Alam, Shaiful and Yamaguchi, Taka and Patel, Yash and Charney, Alexander W. and Kozlitina, Julia and Cohen, Jonathan and Loh, Marie and Katulanda, Prasad and Jha, Vinitaa and Kasturiratne, Anuradhani and Khawaja, Khadija Irfan and Mridha, Malay Kanti and Anjana, Ranjit Mohan and Chambers, John C. and Rader, Daniel J. and Melander, Olle and Still, Christopher D. and Berumen, Jaime and Kuri-Morales, Pablo and Alegre-D{\'\i}az, Jesus and Torres, Jason M. and Emberson, Jonathan R. and Collins, Rory and Tapia-Conyer, Roberto and Balasubramanian, Suganthi and Jones, Marcus B. and LeBlanc, Michelle G. and Murphy, Andrew J. and Kyratsous, Christos A. and Overton, John D. and Reid, Jeffrey G. and Abecasis, Goncalo R. and Marchini, Jonathan and Willer, Cristen and Yancopoulos, George D. and Sleeman, Mark W. and Bovijn, Jonas and Locke, Adam and Baras, Aris and Verweij, Niek and Gusarova, Viktoria and Lotta, Luca A.} }