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 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.