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

• Published in: Nature communications Vol. 12; no. 1; p. 4178
• Main 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.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07-07-2021; Nature Publishing Group; Nature Portfolio
• Subjects: 45; 45/43; 631/208/205/2138; 631/208/211; 692/163/2743/137/773; Adult; Aged; Alleles; Body fat; Carrier Proteins - genetics; Carrier Proteins - metabolism; Case-Control Studies; Chromosomes; Chromosomes, Human, Y - genetics; Deoxyribonucleic acid; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; DNA; DNA damage; DNA Mutational Analysis; Female; Genetic analysis; Genetic Predisposition to Disease; Genome-Wide Association Study; Humanities and Social Sciences; Humans; Insulin; Insulin - metabolism; Insulin-like growth factor I; Leukocytes; Loss of Function Mutation; Male; Metabolism; Middle Aged; Mosaicism; Mosaics; multidisciplinary; Receptor, IGF Type 1 - metabolism; Science; Science (multidisciplinary); Signal transduction; Signal Transduction - genetics; Whole Exome Sequencing
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-24504-y

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.
Mosaic loss of chromosome Y (LOY) is a common form of clonal mosaicism in leukocytes. Here, the authors extend genetic association analyses to rare variation using exome-sequence data from 82,277 males, finding that loss-of-function alleles in
GIGYF1
are associated with six-fold higher susceptibility to both LOY and Type 2 Diabetes.