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size="100%">Chalasani, Naga P.</style></author><author><style face="normal" font="default" size="100%">Schwantes-An, Tae-Hwi L.</style></author><author><style face="normal" font="default" size="100%">Saykin, Andrew J.</style></author><author><style face="normal" font="default" size="100%">Bui, Alex</style></author><author><style face="normal" font="default" size="100%">Petruse, Antonia</style></author><author><style face="normal" font="default" size="100%">Naeim, Arash</style></author><author><style face="normal" font="default" size="100%">Denny, Chris</style></author><author><style face="normal" font="default" size="100%">Lajonchere, Clara</style></author><author><style face="normal" font="default" size="100%">Magyar, Clara</style></author><author><style face="normal" font="default" size="100%">Geschwind, Dan</style></author><author><style face="normal" font="default" size="100%">Ariannejad, Maryam</style></author><author><style face="normal" font="default" size="100%">Boutros, Paul</style></author><author><style face="normal" font="default" size="100%">Spellman, Paul</style></author><author><style face="normal" font="default" size="100%">Dry, Sarah</style></author><author><style face="normal" font="default" size="100%">Nelson, Stan</style></author><author><style face="normal" font="default" size="100%">Duntugan, Albert</style></author><author><style face="normal" font="default" size="100%">Pasaniuc, Bogdan</style></author><author><style face="normal" font="default" size="100%">Tung, Paul</style></author><author><style face="normal" font="default" size="100%">Chang, Tim</style></author><author><style face="normal" font="default" size="100%">Berkovich, Yael</style></author><author><style face="normal" font="default" size="100%">Jain, Ankur</style></author><author><style face="normal" font="default" size="100%">Martinez, Danielle</style></author><author><style face="normal" font="default" size="100%">Mohammed, Ghouse</style></author><author><style face="normal" font="default" size="100%">Illiev, Lora</style></author><author><style face="normal" font="default" size="100%">Broudy, Michael</style></author><author><style face="normal" font="default" size="100%">Haas, Roni</style></author><author><style face="normal" font="default" size="100%">Alam, Shaiful</style></author><author><style face="normal" font="default" size="100%">Yamaguchi, Taka</style></author><author><style face="normal" font="default" size="100%">Patel, Yash</style></author><author><style face="normal" font="default" size="100%">Charney, Alexander W.</style></author><author><style face="normal" font="default" size="100%">Kozlitina, Julia</style></author><author><style face="normal" font="default" size="100%">Cohen, Jonathan</style></author><author><style face="normal" font="default" size="100%">Loh, Marie</style></author><author><style face="normal" font="default" size="100%">Katulanda, Prasad</style></author><author><style face="normal" font="default" size="100%">Jha, Vinitaa</style></author><author><style face="normal" font="default" size="100%">Kasturiratne, Anuradhani</style></author><author><style face="normal" font="default" size="100%">Khawaja, Khadija Irfan</style></author><author><style face="normal" font="default" size="100%">Mridha, Malay Kanti</style></author><author><style face="normal" font="default" size="100%">Anjana, Ranjit Mohan</style></author><author><style face="normal" font="default" size="100%">Chambers, John C.</style></author><author><style face="normal" font="default" size="100%">Rader, Daniel J.</style></author><author><style face="normal" font="default" size="100%">Melander, Olle</style></author><author><style face="normal" font="default" size="100%">Still, Christopher D.</style></author><author><style face="normal" font="default" size="100%">Berumen, Jaime</style></author><author><style face="normal" font="default" size="100%">Kuri-Morales, Pablo</style></author><author><style face="normal" font="default" size="100%">Alegre-Díaz, Jesus</style></author><author><style face="normal" font="default" size="100%">Torres, Jason M.</style></author><author><style face="normal" font="default" size="100%">Emberson, Jonathan R.</style></author><author><style face="normal" font="default" size="100%">Collins, Rory</style></author><author><style face="normal" font="default" size="100%">Tapia-Conyer, Roberto</style></author><author><style face="normal" font="default" size="100%">Balasubramanian, Suganthi</style></author><author><style face="normal" font="default" size="100%">Jones, Marcus B.</style></author><author><style face="normal" font="default" size="100%">LeBlanc, Michelle G.</style></author><author><style face="normal" font="default" size="100%">Murphy, Andrew J.</style></author><author><style face="normal" font="default" size="100%">Kyratsous, Christos A.</style></author><author><style face="normal" font="default" size="100%">Overton, John D.</style></author><author><style face="normal" font="default" size="100%">Reid, Jeffrey G.</style></author><author><style face="normal" font="default" size="100%">Abecasis, Goncalo R.</style></author><author><style face="normal" font="default" size="100%">Marchini, Jonathan</style></author><author><style face="normal" font="default" size="100%">Willer, Cristen</style></author><author><style face="normal" font="default" size="100%">Yancopoulos, George D.</style></author><author><style face="normal" font="default" size="100%">Sleeman, Mark W.</style></author><author><style face="normal" font="default" size="100%">Bovijn, Jonas</style></author><author><style face="normal" font="default" size="100%">Locke, Adam</style></author><author><style face="normal" font="default" size="100%">Baras, Aris</style></author><author><style face="normal" font="default" size="100%">Verweij, Niek</style></author><author><style face="normal" font="default" size="100%">Gusarova, Viktoria</style></author><author><style face="normal" font="default" size="100%">Lotta, Luca A.</style></author></authors></contributors><titles><title><style face="normal" font="default" size="100%">FNIP1 variants are associated with favourable metabolism in 1 million humans</style></title><secondary-title><style face="normal" font="default" size="100%">Nature</style></secondary-title></titles><dates><year><style  face="normal" font="default" size="100%">2026</style></year><pub-dates><date><style  face="normal" font="default" size="100%">2026/08/05</style></date></pub-dates></dates><urls><web-urls><url><style face="normal" font="default" size="100%">https://www.nature.com/articles/s41586-026-10864-2</style></url></web-urls></urls><isbn><style face="normal" font="default" size="100%">0028-08361476-4687</style></isbn><language><style face="normal" font="default" size="100%">eng</style></language><abstract><style face="normal" font="default" size="100%">&lt;p&gt;&lt;meta charset=&quot;UTF-8&quot; /&gt;Altered energy metabolism is a shared driver across 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               (2021).&quot;&gt;8&lt;/a&gt;,&lt;a aria-label=&quot;Reference 9&quot; data-test=&quot;citation-ref&quot; data-track=&quot;click&quot; data-track-action=&quot;reference anchor&quot; data-track-label=&quot;link&quot; href=&quot;https://www.nature.com/articles/s41586-026-10864-2#ref-CR9&quot; id=&quot;ref-link-section-d39962086e4944&quot; title=&quot;Akbari, P. et al. Multiancestry exome sequencing reveals INHBE mutations associated with favorable fat distribution and protection from diabetes. Nat. Commun. 13, 4844 (2022).&quot;&gt;9&lt;/a&gt;&lt;/sup&gt;. Here, to investigate the genetic basis of energy metabolism, we perform an&amp;nbsp;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)&amp;mdash;an energy-state biomarker that we associate with diverse cardiometabolic risk factors and diseases. We identify 59 independent genes (&lt;i&gt;P&lt;/i&gt;&amp;thinsp;&amp;lt;&amp;thinsp;1.04&amp;thinsp;&amp;times;&amp;thinsp;10&lt;sup&gt;&amp;minus;7&lt;/sup&gt;) 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&amp;nbsp;&lt;i&gt;FNIP1&lt;/i&gt;&amp;nbsp;(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.&amp;nbsp;&lt;i&gt;FNIP1&lt;/i&gt;&amp;nbsp;knockdown in primary human hepatocytes induces lipid breakdown and lysosomal gene expression, while combined hepatic knockdown of&amp;nbsp;&lt;i&gt;Fnip1&lt;/i&gt;&amp;nbsp;with its paralogue&amp;nbsp;&lt;i&gt;Fnip2&lt;/i&gt;&amp;nbsp;or knockdown of its interactor&amp;nbsp;&lt;i&gt;Flcn&lt;/i&gt;protect 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.&lt;/p&gt;
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