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

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.

Microvascular and macrovascular complications of type 2 diabetes mellitus: Exome wide association analyses

“…Gene ACVR1C is highly expressed in adipose tissue, and has been associated to extraocular retinoblastoma, hyperkeratosis, T2DM, obesity and anthropometric measurements, such as waist-to-hip ratio and body mass index ( 23 – 25 ). Interestingly, ACVRIC is also associated to lipid profile and glycemic markers ( 26 – 30 ).…”

“…When investigating sub-phenotypes of T2DM, diabetic retinopathy has been identified to be associated with ACVRIC (rs4664229), ZFHX4 (rs61729527), WNT9B (rs4968281), SHANK3 (rs9616915), ZSCAN5A (rs7252603), and DCP1B (rs715146, rs1044950, rs113147414) gene. These genes have intercrossing pathways and similar genetic variants to fibrinogen levels associated to intra-vessel pressure, low platelet count, leukocyte-retinal endothelial cell adhesion, metabolite levels and glycemic markers, all important factors impacting intra-retinal microvascular abnormalities, retinal capillaries and variations of eye-related diseases ( 23 – 30 , 37 , 40 – 44 ). For diabetic neuropathy, gene GFY (rs4802605), ADH4 (rs4148883), LRFN2 (rs61731010), PKHD1 (rs2499486), SLC11A1 (rs17235409), MATN4 (rs2072788), and PPARA (rs4253772) were associated or contributed to the biological relevance to the pathogenesis of the complication.…”

The GDF3-ALK7 signaling axis in adipose tissue: a possible therapeutic target for obesity and associated diabetes?

“…It remains unknown from which cells activin B or C is derived to act on ALK7 in adipocytes. On the other hand, mutations of genes encoding hepatokine, activin E, and ALK7 are commonly associated with fat distribution and diabetes risk in humans [31,32], although there is no direct biochemical evidence for their ligand-receptor relationship.…”

“…A recent work using inhibitors of Smad Activin AB, B, and C can activate ALK7 signaling both in heterologous cells and in adipocytes [5,23,30], although it is unknown from which cells these activins are derived to act on ALK7 in vivo. Variants in activin E produced from liver and ALK7 are associated with a lower waist-to-hip ratio in humans [31,32], although there is no direct evidence for the ligand-receptor relationship between them. GDF3 can also activate ALK7 signaling both in heterologous cells and in adipocytes [11,25].…”

From Genes to Geography, from Cells to Community, from Biomolecules to Behaviors: The Importance of Social Determinants of Health

“…How mHealth and digital devices will feed into SDOH is still an active area of research. Other newer sources of SDOH-related data will also include genomic information for large populations uploaded to EHR databases, which is already being implemented by various institutions around the country [ 26 ].…”