A joint view on genetic variants for adiposity differentiates subtypes with distinct metabolic implications

Nat Commun. 2018 May 16;9(1):1946. doi: 10.1038/s41467-018-04124-9.


The problem of the genetics of related phenotypes is often addressed by analyzing adjusted-model traits, but such traits warrant cautious interpretation. Here, we adopt a joint view of adiposity traits in ~322,154 subjects (GIANT consortium). We classify 159 signals associated with body mass index (BMI), waist-to-hip ratio (WHR), or WHR adjusted for BMI (WHRadjBMI) at P < 5 × 10-8, into four classes based on the direction of their effects on BMI and WHR. Our classes help differentiate adiposity genetics with respect to anthropometry, fat depots, and metabolic health. Class-specific Mendelian randomization reveals that variants associated with both WHR-decrease and BMI increase are linked to metabolically rather favorable adiposity through beneficial hip fat. Class-specific enrichment analyses implicate digestive systems as a pathway in adiposity genetics. Our results demonstrate that WHRadjBMI variants capture relevant effects of "unexpected fat distribution given the BMI" and that a joint view of the genetics underlying related phenotypes can inform on important biology.

Publication types

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

MeSH terms

  • Adipose Tissue / metabolism
  • Adiposity / genetics*
  • Body Mass Index*
  • Energy Metabolism / genetics
  • Genetic Variation*
  • Genome-Wide Association Study / methods
  • Humans
  • Meta-Analysis as Topic
  • Obesity / classification
  • Obesity / genetics
  • Obesity / metabolism
  • Polymorphism, Single Nucleotide
  • Waist-Hip Ratio*