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

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 Diabet

SUBMITTER: Zhao Y 

PROVIDER: S-EPMC8263756 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature