GIGYF1 loss of function is associated with clonal mosaicism and adverse metabolic health
Lango Allen, Hana
Kerrison, Nicola D.
Nature Publishing Group UK
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Zhao, Y., Stankovic, S., Koprulu, M., Wheeler, E., Day, F. R., Lango Allen, H., Kerrison, N. D., et al. (2021). GIGYF1 loss of function is associated with clonal mosaicism and adverse metabolic health. Nature Communications, 12 (1)https://doi.org/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.
Article, /631/208/205/2138, /631/208/211, /692/163/2743/137/773, /45, /45/43, article
RCUK | Medical Research Council (MRC) (MC_UU_00006/2)
External DOI: https://doi.org/10.1038/s41467-021-24504-y
This record's URL: https://www.repository.cam.ac.uk/handle/1810/324926