Title: GIGYF1 loss of function is associated with clonal mosaicism and adverse metabolic health.
Authors: Zhao, Yajie; Stankovic, Stasa; Koprulu, Mine; Wheeler, Eleanor; Day, Felix R; Lango Allen, Hana; Kerrison, Nicola D; Pietzner, Maik; Loh, Po-Ru; Wareham, Nicholas J; Langenberg, Claudia; Ong, Ken K; Perry, John R B
Published In Nat Commun, (2021 07 07)
Abstract: Mosaic loss of chromosome Y (LOY) in leukocytes is the most common form of clonal mosaicism, caused by dysregulation in cell-cycle and DNA damage response pathways. Previous genetic studies have focussed on identifying common variants associated with LOY, which we now extend to rarer, protein-coding variation using exome sequences from 82,277 male UK Biobank participants. We find that loss of function of two genes-CHEK2 and GIGYF1-reach exome-wide significance. Rare alleles in GIGYF1 have not previously been implicated in any complex trait, but here loss-of-function carriers exhibit six-fold higher susceptibility to LOY (OR = 5.99 [3.04-11.81], p = 1.3 × 10-10). These same alleles are also associated with adverse metabolic health, including higher susceptibility to Type 2 Diabetes (OR = 6.10 [3.51-10.61], p = 1.8 × 10-12), 4 kg higher fat mass (p = 1.3 × 10-4), 2.32 nmol/L lower serum IGF1 levels (p = 1.5 × 10-4) and 4.5 kg lower handgrip strength (p = 4.7 × 10-7) consistent with proposed GIGYF1 enhancement of insulin and IGF-1 receptor signalling. These associations are mirrored by a common variant nearby associated with the expression of GIGYF1. Our observations highlight a potential direct connection between clonal mosaicism and metabolic health.
PubMed ID: 34234147
MeSH Terms: Adult; Aged; Carrier Proteins/genetics*; Carrier Proteins/metabolism; Case-Control Studies; Chromosomes, Human, Y/genetics*; DNA Mutational Analysis; Diabetes Mellitus, Type 2/genetics*; Diabetes Mellitus, Type 2/metabolism; Female; Genetic Predisposition to Disease*; Genome-Wide Association Study; Humans; Insulin/metabolism; Leukocytes; Loss of Function Mutation; Male; Middle Aged; Mosaicism*; Receptor, IGF Type 1/metabolism; Signal Transduction/genetics; Whole Exome Sequencing