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

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, proteincoding 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.

Automated summary

Obesity has a significant heritable component, and recent studies have identified genes that have a large effect on adult BMI. By performing sex-stratified associations in the UK Biobank study, researchers discovered several genes that increase adult BMI in women (DIDO1, PTPRG, and SLC12A5) and in men (SLTM) with large effect sizes. Analyses also implicated rare variants in OBSCN and MADD for childhood adiposity. These findings suggest the involvement of neuron death, apoptosis, and DNA damage response mechanisms in obesity susceptibility across the life-course.