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

Accepted version
Peer-reviewed

Type

Article

Change log

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.

Description

Keywords

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

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

12

Publisher

Springer Science and Business Media LLC

Rights

All rights reserved
Sponsorship
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.