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

Nature Communications
Thomas W WinklerIris M Heid

Abstract

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.

References

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Citations

Jan 24, 2020·Current Diabetes Reports·Jonathan SulcZoltán Kutalik
Feb 12, 2020·Gastroenterology·Mohammed EslamUNKNOWN International Consensus Panel
Aug 29, 2021·International Journal of Obesity : Journal of the International Association for the Study of Obesity·Muktar AhmedElina Hyppönen

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Methods Mentioned

BETA
imaging techniques
chip

Software Mentioned

PLINK
GIANT
UKBB
R package EasyStrata
R
Metabochip
DEPICT
FUMA
scripts
EasyStrata

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