Large-scale exome sequence analysis identifies sex- and age-specific determinants of obesity.
Cell genomics 2023 ; 3: 100362.
Kaisinger LR, Kentistou KA, Stankovic S, Gardner EJ, Day FR, Zhao Y, Mörseburg A, Carnie CJ, Zagnoli-Vieira G, Puddu F, Jackson SP, O'Rahilly S, Farooqi IS, Dearden L, Pantaleão LC, Ozanne SE, Ong KK, Perry JRB
PubMed ID : 37601970
PMCID : PMC10435378
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 ( and ) and in men (), with effect sizes up to ∼8 kg/m. This is complemented by analyses implicating rare variants in and 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.