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

Yajie Zhao, Stasa Stankovic, Mine Koprulu, Eleanor Wheeler, Felix R. Day, Hana Lango Allen, Nicola D. Kerrison, Maik Pietzner, Po-Ru Loh, Nicholas J. Wareham, Claudia Langenberg, Ken K. Ong and John R. B. Perry ()
Additional contact information
Yajie Zhao: University of Cambridge
Stasa Stankovic: University of Cambridge
Mine Koprulu: University of Cambridge
Eleanor Wheeler: University of Cambridge
Felix R. Day: University of Cambridge
Hana Lango Allen: University of Cambridge
Nicola D. Kerrison: University of Cambridge
Maik Pietzner: University of Cambridge
Po-Ru Loh: Brigham and Women’s Hospital and Harvard Medical School
Nicholas J. Wareham: University of Cambridge
Claudia Langenberg: University of Cambridge
Ken K. Ong: University of Cambridge
John R. B. Perry: University of Cambridge

Nature Communications, 2021, vol. 12, issue 1, 1-6

Abstract: 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.

Date: 2021
References: Add references at CitEc
Citations: View citations in EconPapers (2)

Downloads: (external link)
https://www.nature.com/articles/s41467-021-24504-y Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24504-y

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-021-24504-y

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().