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GIGYF1 loss of function is associated with clonal mosaicism and adverse metabolic health.

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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.



Adult, Aged, Carrier Proteins, Case-Control Studies, Chromosomes, Human, Y, DNA Mutational Analysis, Diabetes Mellitus, Type 2, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Insulin, Leukocytes, Loss of Function Mutation, Male, Middle Aged, Mosaicism, Receptor, IGF Type 1, Signal Transduction, Exome Sequencing

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Nat Commun

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Springer Science and Business Media LLC


All rights reserved
MRC (MC_UU_00006/2)
MRC (MC_UU_00006/1)
Medical Research Council (MC_UU_12015/1)
Medical Research Council (MC_UU_12015/2)
All Cambridge (UK) authors are supported by the Medical Research Council (Unit programmes: MC_UU_12015/2, MC_UU_00006/2, MC_UU_12015/1 and MC_UU_00006/1). NJW is a NIHR Senior Investigator. P.-R.L. is supported by NIH grant DP2 ES030554 and a Burroughs Wellcome Fund Career Award at the Scientific Interfaces. This research was conducted using the UK Biobank Resource under application 9905.