Large-scale exome sequence analysis identifies sex- and age-specific determinants of obesity.

Abstract:: Obesity contributes substantially to the global burden of disease and has a significant heritable component. Recent large-scale exome sequencing studies identified several genes in which rare, protein-coding variants have large effects on adult body mass index (BMI). Here we extended such work by performing sex-stratified associations in the UK Biobank study (N∼420,000). We identified genes in which rare heterozygous loss-of-function increases adult BMI in women (DIDO1, PTPRG, and SLC12A5) and in men (SLTM), with effect sizes up to ∼8 kg/m2. This is complemented by analyses implicating rare variants in OBSCN and MADD for recalled childhood adiposity. The known functions of these genes, as well as findings of common variant genome-wide pathway enrichment analyses, suggest a role for neuron death, apoptosis, and DNA damage response mechanisms in the susceptibility to obesity across the life-course. These findings highlight the importance of considering sex-specific and life-course effects in the genetic regulation of obesity.

Authors:: LR Kaisinger, KA Kentistou, S Stankovic, EJ Gardner, FR Day, Y Zhao, A Mörseburg, CJ Carnie, G Zagnoli-Vieira, F Puddu, SP Jackson, S O'Rahilly, IS Farooqi, L Dearden, LC Pantaleão, SE Ozanne, KK Ong, JRB Perry

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