“Large-Scale Exome Sequence Analysis Identifies Sex- and Age-Specific Determinants of Obesity”, Lena R. Kaisinger, Katherine A. Kentistou, Stasa Stankovic, Eugene J. Gardner, Felix R. Day, Yajie Zhao, Alexander Mörseburg, Christopher J. Carnie, Guido Zagnoli-Vieira, Fabio Puddu, Stephen P. Jackson, Stephen O’Rahilly, I. Sadaf Farooqi, Laura Dearden, Lucas C. Pantaleão, Susan E. Ozanne, Ken K. Ong, John R. B. Perry2023 (exercise, rare mutations)⁠:

[commentary] Obesity contributes substantially to the global burden of disease and has a large 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.