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

• DOI: 10.1038/s41467-021-24504-y
• Publication Date: 2021-07-07T10:04:07Z
• 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
• Keywords: Exome; Loss function

Abstract Mosaic loss of chromosome Y (LOY) in leukocytes is the most common form clonal mosaicism, caused by dysregulation cell-cycle and DNA damage response pathways. Previous genetic studies have focussed on identifying 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 function two genes— CHEK2 GIGYF1 —reach exome-wide significance. Rare alleles not previously been implicated any complex trait, but here loss-of-function carriers exhibit six-fold higher susceptibility LOY (OR = 5.99 [3.04–11.81], p 1.3 × 10 −10 ). These same are also adverse metabolic health, including Type 2 Diabetes 6.10 [3.51–10.61], 1.8 −12 ), 4 kg fat mass ( −4 2.32 nmol/L lower serum IGF1 levels 1.5 ) 4.5 handgrip strength 4.7 −7 consistent proposed enhancement insulin IGF-1 receptor signalling. associations mirrored a variant nearby expression . Our observations highlight potential direct connection between mosaicism health.