| Title: | GIGYF1 loss of function is associated with clonal mosaicism and adverse metabolic health |
| Journal: | Nature Communications |
| Published: | 7 Jul 2021 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/34234147/ |
| DOI: | https://doi.org/10.1038/s41467-021-24504-y |
| URL: | https://www.nature.com/articles/s41467-021-24504-y.pdf |
Publication 5085
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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.</p>
13 Authors
- 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
- John R. B. Perry
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