FNIP1 variants are associated with favourable 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., Hunt C., 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 JM., 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., Willer C., Yancopoulos GD., Sleeman MW., Bovijn J., Locke A., Baras A., Verweij N., Gusarova V., Lotta LA.
Altered energy metabolism is a shared driver across cardiometabolic diseases-the leading cause of death globally1. Energy metabolism varies between individuals and is partly heritable2-9. 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 Flcn 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.