Identification of Rare Loss-of-Function Genetic Variation Regulating Body Fat Distribution

Mine Koprulu, Yajie Zhao, Eleanor Wheeler, Liang Dong, Nuno Rocha, Chen Li, John D. Griffin, Satish Patel, Marcel Van De Streek, Craig A. Glastonbury, Isobel D. Stewart, Felix R. Day, Jian'an Luan, Nicholas Bowker, Laura B.L. Wittemans, Nicola D. Kerrison, Lina Cai, Debora M.E. Lucarelli, Inês Barroso, Mark I. McCarthyRobert A. Scott, Vladimir Saudek, Kerrin S. Small, Nicholas J. Wareham, Robert K. Semple, John R.B. Perry, Stephen O'Rahilly, Luca A. Lotta, Claudia Langenberg*, David B. Savage

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

Abstract

Context: Biological and translational insights from large-scale, array-based genetic studies of fat distribution, a key determinant of metabolic health, have been limited by the difficulty in linking predominantly noncoding variants to specific gene targets. Rare coding variant analyses provide greater confidence that a specific gene is involved, but do not necessarily indicate whether gain or loss of function (LoF) would be of most therapeutic benefit. Objective: This work aimed to identify genes/proteins involved in determining fat distribution. Methods: We combined the power of genome-wide analysis of array-based rare, nonsynonymous variants in 450562 individuals in the UK Biobank with exome-sequence-based rare LoF gene burden testing in 184246 individuals. Results: The data indicate that the LoF of 4 genes (PLIN1 [LoF variants, P=5.86×10-7], INSR [LoF variants, P=6.21×10-7], ACVR1C [LoF+moderate impact variants, P=1.68×10-7; moderate impact variants, P=4.57×10-7], and PDE3B [LoF variants, P=1.41×10-6]) is associated with a beneficial effect on body mass index-adjusted waist-to-hip ratio and increased gluteofemoral fat mass, whereas LoF of PLIN4 (LoF variants, P=5.86×10-7 adversely affects these parameters. Phenotypic follow-up suggests that LoF of PLIN1, PDE3B, and ACVR1C favorably affects metabolic phenotypes (eg, triglycerides [TGs] and high-density lipoprotein [HDL] cholesterol concentrations) and reduces the risk of cardiovascular disease, whereas PLIN4 LoF has adverse health consequences. INSR LoF is associated with lower TG and HDL levels but may increase the risk of type 2 diabetes. Conclusion: This study robustly implicates these genes in the regulation of fat distribution, providing new and in some cases somewhat counterintuitive insight into the potential consequences of targeting these molecules therapeutically.

Original languageEnglish
Pages (from-to)1065-1077
Number of pages13
JournalJournal of Clinical Endocrinology and Metabolism
Volume107
Issue number4
DOIs
Publication statusPublished - 1 Apr 2022

Keywords

  • cardiometabolic risk
  • fat distribution
  • genetic variants
  • loss of function
  • UK Biobank

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