Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance

Publication type

Journal Article

Published in

Nature Genetics

Authors

Luca A. Lotta, Pawan Gulati, Felix R. Day, Felicity Payne, Halit Ongen, Martijn van de Bunt, Kyle J. Gaulton, John D. Eicher, Stephen J. Sharp, Jian'an Luan, Emanuella De Lucia Rolfe, Isobel D. Stewart, Eleanor Wheeler, Sara M. Willems, Claire Adams, Hanieh Yaghootkar, Nita G. Forouhi, Kay-Tee Khaw, Andrew D. Johnson, Robert K. Semple, Timothy Frayling, John R. B. Perry, Emmanouil Dermitzakis, Mark I. McCarthy, Ines Barroso, Nicholas J. Wareham, David B. Savage, Claudia Langenberg, Stephen O'Rahilly and Robert A. Scott

Publication date

Summary

Insulin resistance is a key mediator of obesity-related cardiometabolic disease, yet the mechanisms underlying this link remain obscure. Using an integrative genomic approach, we identify 53 genomic regions associated with insulin resistance phenotypes (higher fasting insulin levels adjusted for BMI, lower HDL cholesterol levels and higher triglyceride levels) and provide evidence that their link with higher cardiometabolic risk is underpinned by an association with lower adipose mass in peripheral compartments. Using these 53 loci, we show a polygenic contribution to familial partial lipodystrophy type 1, a severe form of insulin resistance, and highlight shared molecular mechanisms in common/mild and rare/severe insulin resistance. Population-level genetic analyses combined with experiments in cellular models implicate CCDC92, DNAH10 and L3MBTL3 as previously unrecognized molecules influencing adipocyte differentiation. Our findings support the notion that limited storage capacity of peripheral adipose tissue is an important etiological component in insulin-resistant cardiometabolic disease and highlight genes and mechanisms underpinning this link.

Volume and page numbers

49, 17-26

DOI

http://dx.doi.org/10.1038/ng.3714

ISSN

16

Subjects

Medicine, Science And Technology, Health, Biology and Genetics

Notes

Not held in Hilary Doughty Research Library - bibliographic reference only

Related Publications

  1. Corrigendum: integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance