Multiancestry exome sequencing reveals INHBE mutations associated with favorable fat distribution and protection from diabetes

Parsa Akbari, Olukayode A. Sosina, Jonas Bovijn, Karl Landheer, Jonas B. Nielsen, Minhee Kim, Senem Aykul, Tanima De, Mary E. Haas, George Hindy, Nan Lin, Ian R. Dinsmore, Jonathan Z. Luo, Stefanie Hectors, Benjamin Geraghty, Mary Germino, Lampros Panagis, Prodromos Parasoglou, Johnathon R. Walls, Gabor Halasz, Gurinder S. Atwal, Marcus Jones, Michelle G. LeBlanc, Christopher D. Still, David J. Carey, Alice Giontella, Marju Orho-Melander, Jaime Berumen, Pablo Kuri-Morales, Jesus Alegre-Díaz, Jason M. Torres, Jonathan R. Emberson, Rory Collins, Daniel J. Rader, Brian Zambrowicz, Andrew J. Murphy, Suganthi Balasubramanian, John D. Overton, Jeffrey G. Reid, Alan R. Shuldiner, Michael Cantor, Goncalo R. Abecasis, Manuel A. R. Ferreira, Mark W. Sleeman, Viktoria Gusarova, Judith Altarejos, Charles Harris, Aris N. Economides, Vincent Idone, Katia Karalis, Giusy Gatta, Tooraj Mirshahi, George D. Yancopoulos, Olle Melander, Jonathan Marchini, Roberto Tapia-Conyer, Adam E. Locke, Aris Baras (), Niek Verweij and Luca A. Lotta ()
Additional contact information
Parsa Akbari: Regeneron Pharmaceuticals Inc
Olukayode A. Sosina: Regeneron Pharmaceuticals Inc
Jonas Bovijn: Regeneron Pharmaceuticals Inc
Karl Landheer: Regeneron Pharmaceuticals Inc
Jonas B. Nielsen: Regeneron Pharmaceuticals Inc
Minhee Kim: Regeneron Pharmaceuticals Inc
Senem Aykul: Regeneron Pharmaceuticals Inc
Tanima De: Regeneron Pharmaceuticals Inc
Mary E. Haas: Regeneron Pharmaceuticals Inc
George Hindy: Regeneron Pharmaceuticals Inc
Nan Lin: Regeneron Pharmaceuticals Inc
Ian R. Dinsmore: Geisinger Health System
Jonathan Z. Luo: Geisinger Health System
Stefanie Hectors: Regeneron Pharmaceuticals Inc
Benjamin Geraghty: Regeneron Pharmaceuticals Inc
Mary Germino: Regeneron Pharmaceuticals Inc
Lampros Panagis: Regeneron Pharmaceuticals Inc
Prodromos Parasoglou: Regeneron Pharmaceuticals Inc
Johnathon R. Walls: Regeneron Pharmaceuticals Inc
Gabor Halasz: Regeneron Pharmaceuticals Inc
Gurinder S. Atwal: Regeneron Pharmaceuticals Inc
Marcus Jones: Regeneron Pharmaceuticals Inc
Michelle G. LeBlanc: Regeneron Pharmaceuticals Inc
Christopher D. Still: Geisinger Health System
David J. Carey: Geisinger Health System
Alice Giontella: Lund University
Marju Orho-Melander: Lund University
Jaime Berumen: Unidad de Medicina Experimental de la Facultad de Medicina de la Universidad Nacional Autónoma de México
Pablo Kuri-Morales: Unidad de Medicina Experimental de la Facultad de Medicina de la Universidad Nacional Autónoma de México
Jesus Alegre-Díaz: Unidad de Medicina Experimental de la Facultad de Medicina de la Universidad Nacional Autónoma de México
Jason M. Torres: University of Oxford
Jonathan R. Emberson: University of Oxford
Rory Collins: University of Oxford
Daniel J. Rader: University of Pennsylvania
Brian Zambrowicz: Regeneron Pharmaceuticals Inc
Andrew J. Murphy: Regeneron Pharmaceuticals Inc
Suganthi Balasubramanian: Regeneron Pharmaceuticals Inc
John D. Overton: Regeneron Pharmaceuticals Inc
Jeffrey G. Reid: Regeneron Pharmaceuticals Inc
Alan R. Shuldiner: Regeneron Pharmaceuticals Inc
Michael Cantor: Regeneron Pharmaceuticals Inc
Goncalo R. Abecasis: Regeneron Pharmaceuticals Inc
Manuel A. R. Ferreira: Regeneron Pharmaceuticals Inc
Mark W. Sleeman: Regeneron Pharmaceuticals Inc
Viktoria Gusarova: Regeneron Pharmaceuticals Inc
Judith Altarejos: Regeneron Pharmaceuticals Inc
Charles Harris: Regeneron Pharmaceuticals Inc
Aris N. Economides: Regeneron Pharmaceuticals Inc
Vincent Idone: Regeneron Pharmaceuticals Inc
Katia Karalis: Regeneron Pharmaceuticals Inc
Giusy Gatta: Regeneron Pharmaceuticals Inc
Tooraj Mirshahi: Geisinger Health System
George D. Yancopoulos: Regeneron Pharmaceuticals Inc
Olle Melander: Lund University
Jonathan Marchini: Regeneron Pharmaceuticals Inc
Roberto Tapia-Conyer: Instituto Tecnológico y de Estudios Superiores de Monterrey
Adam E. Locke: Regeneron Pharmaceuticals Inc
Aris Baras: Regeneron Pharmaceuticals Inc
Niek Verweij: Regeneron Pharmaceuticals Inc
Luca A. Lotta: Regeneron Pharmaceuticals Inc

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-32398-7

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