Inherited basis of visceral, abdominal subcutaneous and gluteofemoral fat depots

Saaket Agrawal; Minxian Wang; Marcus D R Klarqvist; Kirk Smith; Joseph Shin; Hesam Dashti; Nathaniel Diamant; Seung Hoan Choi; Sean J Jurgens; Patrick T Ellinor; Anthony Philippakis; Melina Claussnitzer; Kenney Ng; Miriam S Udler; Puneet Batra; Amit V Khera

doi:10.1038/s41467-022-30931-2

Inherited basis of visceral, abdominal subcutaneous and gluteofemoral fat depots

Nat Commun. 2022 Jun 30;13(1):3771. doi: 10.1038/s41467-022-30931-2.

Authors

Saaket Agrawal^#^{1

2

3}, Minxian Wang^#^{1

2

4}, Marcus D R Klarqvist⁵, Kirk Smith^{1

2

3}, Joseph Shin^{1

2}, Hesam Dashti¹, Nathaniel Diamant⁵, Seung Hoan Choi^{1

2}, Sean J Jurgens^{1

2

6}, Patrick T Ellinor^{1

2

3}, Anthony Philippakis^{5

7}, Melina Claussnitzer^{1

2

3}, Kenney Ng⁸, Miriam S Udler^{1

2

3}, Puneet Batra⁵, Amit V Khera^{9

10

11

12}

Affiliations

¹ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
² Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
³ Department of Medicine, Harvard Medical School, Boston, MA, USA.
⁴ CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
⁵ Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁶ Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
⁷ Eric and Wendy Schmidt Center, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁸ Center for Computational Health, IBM Research, Cambridge, MA, USA.
⁹ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. avkhera@mgh.harvard.edu.
¹⁰ Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. avkhera@mgh.harvard.edu.
¹¹ Department of Medicine, Harvard Medical School, Boston, MA, USA. avkhera@mgh.harvard.edu.
¹² Verve Therapeutics, Cambridge, MA, USA. avkhera@mgh.harvard.edu.

^# Contributed equally.

Abstract

For any given level of overall adiposity, individuals vary considerably in fat distribution. The inherited basis of fat distribution in the general population is not fully understood. Here, we study up to 38,965 UK Biobank participants with MRI-derived visceral (VAT), abdominal subcutaneous (ASAT), and gluteofemoral (GFAT) adipose tissue volumes. Because these fat depot volumes are highly correlated with BMI, we additionally study six local adiposity traits: VAT adjusted for BMI and height (VATadj), ASATadj, GFATadj, VAT/ASAT, VAT/GFAT, and ASAT/GFAT. We identify 250 independent common variants (39 newly-identified) associated with at least one trait, with many associations more pronounced in female participants. Rare variant association studies extend prior evidence for PDE3B as an important modulator of fat distribution. Local adiposity traits (1) highlight depot-specific genetic architecture and (2) enable construction of depot-specific polygenic scores that have divergent associations with type 2 diabetes and coronary artery disease. These results - using MRI-derived, BMI-independent measures of local adiposity - confirm fat distribution as a highly heritable trait with important implications for cardiometabolic health outcomes.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Adipose Tissue
Adiposity / genetics
Body Mass Index
Diabetes Mellitus, Type 2* / metabolism
Female
Humans
Intra-Abdominal Fat* / diagnostic imaging
Intra-Abdominal Fat* / metabolism
Obesity / metabolism
Subcutaneous Fat / diagnostic imaging
Subcutaneous Fat / metabolism

Abstract

Publication types

MeSH terms

Grants and funding