Multiancestry exome sequencing reveals INHBE mutations associated with favorable fat distribution and protection from diabetes.
Akbari P., Sosina OA., Bovijn J., Landheer K., Nielsen JB., Kim M., Aykul S., De T., Haas ME., Hindy G., Lin N., Dinsmore IR., Luo JZ., Hectors S., Geraghty B., Germino M., Panagis L., Parasoglou P., Walls JR., Halasz G., Atwal GS., Regeneron Genetics Center None., DiscovEHR Collaboration None., Jones M., LeBlanc MG., Still CD., Carey DJ., Giontella A., Orho-Melander M., Berumen J., Kuri-Morales P., Alegre-Díaz J., Torres JM., Emberson JR., Collins R., Rader DJ., Zambrowicz B., Murphy AJ., Balasubramanian S., Overton JD., Reid JG., Shuldiner AR., Cantor M., Abecasis GR., Ferreira MAR., Sleeman MW., Gusarova V., Altarejos J., Harris C., Economides AN., Idone V., Karalis K., Della Gatta G., Mirshahi T., Yancopoulos GD., Melander O., Marchini J., Tapia-Conyer R., Locke AE., Baras A., Verweij N., Lotta LA.
Body fat distribution is a major, heritable risk factor for cardiometabolic disease, independent of overall adiposity. Using exome-sequencing in 618,375 individuals (including 160,058 non-Europeans) from the UK, Sweden and Mexico, we identify 16 genes associated with fat distribution at exome-wide significance. We show 6-fold larger effect for fat-distribution associated rare coding variants compared with fine-mapped common alleles, enrichment for genes expressed in adipose tissue and causal genes for partial lipodystrophies, and evidence of sex-dimorphism. We describe an association with favorable fat distribution (p = 1.8 × 10-09), favorable metabolic profile and protection from type 2 diabetes (~28% lower odds; p = 0.004) for heterozygous protein-truncating mutations in INHBE, which encodes a circulating growth factor of the activin family, highly and specifically expressed in hepatocytes. Our results suggest that inhibin βE is a liver-expressed negative regulator of adipose storage whose blockade may be beneficial in fat distribution-associated metabolic disease.