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

Yajie Zhao,Eleanor Wheeler,Felix R Day,Nicola D Kerrison,Po-Ru Loh,Claudia Langenberg,Maik Pietzner,Mine Koprulu,John R B Perry,Hana Lango Allen,Ken K Ong,Stasa Stankovic,Nicholas J Wareham

doi:10.1038/s41467-021-24504-y

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.

Highlights

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 studies have quantified LOY using either a quantitative measure derived from the mean log2-transformed R ratio of signal intensity[11] or more recently a more-powered dichotomous measure (PAR-LOY) using allele-specific genotyping intensities in the sex chromosome pseudo-autosomal region (PAR)[13]
Rare variants in PDX1, CCND2, SLC30A8, and PAM are associated with double the odds of T2D21–23, whereas GIGYF1 loss of function is associated with a six-fold increased risk (OR = 5.96 [3.43–10.38])

Summary

Introduction

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. These same alleles are 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. Identifying novel genetic determinants associated with LOY has the potential, to increase our knowledge of clonal hematopoiesis and to identify loci that underlie susceptibility to other complex traits through shared biological mechanisms We previously demonstrated this with Type 2 Diabetes (T2D), where overlap with LOY highlights loci which likely impact cellular homeostasis in metabolic tissues. We extend and confirm previous observations supporting the role of CHEK2 and identify an association with GIGYF1 loss of function, highlighting an intriguing link between LOY and metabolic health

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Results

Conclusion