Genetic Evidence for Different Adiposity Phenotypes and Their Opposing Influences on Ectopic Fat and Risk of Cardiometabolic Disease

Abstract

To understand the causal role of adiposity and ectopic fat in type 2 diabetes and cardiometabolic diseases, we aimed to identify two clusters of adiposity genetic variants: one with “adverse” metabolic effects (UFA) and the other with, paradoxically, “favorable” metabolic effects (FA). We performed a multivariate genome-wide association study using body fat percentage and metabolic biomarkers from UK Biobank and identified 38 UFA and 36 FA variants. Adiposity-increasing alleles were associated with an adverse metabolic profile, higher risk of disease, higher CRP, and higher fat in subcutaneous and visceral adipose tissue, liver, and pancreas for UFA and a favorable metabolic profile, lower risk of disease, higher CRP and higher subcutaneous adipose tissue but lower liver fat for FA. We detected no sexual dimorphism. The Mendelian randomization studies provided evidence for a risk-increasing effect of UFA and protective effect of FA for type 2 diabetes, heart disease, hypertension, stroke, nonalcoholic fatty liver disease, and polycystic ovary syndrome. FA is distinct from UFA by its association with lower liver fat and protection from cardiometabolic diseases; it was not associated with visceral or pancreatic fat. Understanding the difference in FA and UFA may lead to new insights in preventing, predicting, and treating cardiometabolic diseases.

Disease consequences of higher adiposity uncoupled from its adverse metabolic effects using Mendelian randomisation

“…We used 696 variants from a GWAS in the UK Biobank ( Martin et al, 2021 ). We used bio-impedance measures of body fat % taken by the Tanita BC-418MA body composition analyser in 442,278 individuals of European ancestry.…”

“…We also identified 38 unfavourable adiposity (UFA) alleles which are associated with higher fat in subcutaneous and visceral adipose tissue, and higher ectopic liver and pancreatic fat ( Ji et al, 2019 ; Martin et al, 2021 ), resembling monogenic obesity ( Supplementary file 1a ). We performed MR studies and showed that FA and UFA have opposite causal effects on six metabolic conditions ( Martin et al, 2021 ). While both FA and UFA were associated with higher adiposity, FA was causally associated with lower risk of type 2 diabetes, heart disease, hypertension, stroke, polycystic ovary syndrome, and non-alcoholic fatty liver disease.…”

“…For example, several studies have characterised variants associated with ‘favourable adiposity’ (FA) or reduced adipose storage capacity using a variety of approaches ( Ji et al, 2019 ; Lotta et al, 2017 ; Kilpeläinen et al, 2011 ; Huang et al, 2021 ). We recently identified 36 FA alleles which are collectively associated with a favourable metabolic profile, higher subcutaneous fat but lower ectopic liver fat ( Ji et al, 2019 ; Martin et al, 2021 ), resembling a polygenic phenotype opposite to lipodystrophy ( Semple et al, 2011 ). We also identified 38 unfavourable adiposity (UFA) alleles which are associated with higher fat in subcutaneous and visceral adipose tissue, and higher ectopic liver and pancreatic fat ( Ji et al, 2019 ; Martin et al, 2021 ), resembling monogenic obesity ( Supplementary file 1a ).…”

“…We recently identified 36 FA alleles which are collectively associated with a favourable metabolic profile, higher subcutaneous fat but lower ectopic liver fat ( Ji et al, 2019 ; Martin et al, 2021 ), resembling a polygenic phenotype opposite to lipodystrophy ( Semple et al, 2011 ). We also identified 38 unfavourable adiposity (UFA) alleles which are associated with higher fat in subcutaneous and visceral adipose tissue, and higher ectopic liver and pancreatic fat ( Ji et al, 2019 ; Martin et al, 2021 ), resembling monogenic obesity ( Supplementary file 1a ). We performed MR studies and showed that FA and UFA have opposite causal effects on six metabolic conditions ( Martin et al, 2021 ).…”

Inherited basis of visceral, abdominal subcutaneous and gluteofemoral fat depots

“…16,17 A second category of studies has aimed to gain further resolution into anthropometric loci by combining summary statistics of metabolic and anthropometric traits, generating clusters of metabolically favorable and unfavorable loci. [18][19][20][21][22] These studies have succeeded in establishing a common variant basis for metabolically distinct fat depots, with seminal work demonstrating that an insulin resistance polygenic score is associated with lower hip circumference in the general population, and that individuals with familial partial lipodystrophy type 1 (FPLD1) have a higher burden of this polygenic score. 19 Along with their reliance on anthropometric proxies of fat distribution, these studies are limited by their inclusion requirement of nominal significance across multiple metabolic traits which is likely leading to only a fraction of the genetic architecture of fat distribution being described.…”