Interactions between genes and environmental factors like diet determine people’s weight and body size. Now, new research that looked at data from over 400,000 adults suggests that the effects of some genes on obesity risk depend on the biological sex and age of the individual.
Full details of the findings are provided in a paper titled, “Large-scale exome sequence analysis identifies sex- and age-specific determinants of obesity” published in Cell Genomics. For the study, the researchers looked at exome data from nearly 420,000 adult participants in the UK Biobank study. They looked at mutations in genes associated with body mass index (BMI) in men and women, and for gene variants associated with participants’ reported body size at age 10.
Obesity is a growing problem around the world. In the United States alone, the estimated annual medical cost of obesity was nearly $173 billion in 2019. According to 2017–2018 data from the National Institute of Diabetes and Digestive and Kidney Diseases, over 30% of U.S. adults were overweight, 42.4% were classified as obese, and 9.2% had severe obesity. According to the World Health Organization, in 2016 about 650 million adults were considered obese. Large population studies like this one can elucidate important pathways that could one day be targets for drugs aimed at treating obesity.
“What’s quite surprising is that if you look at the function of some of these genes that we identified, several are clearly involved in DNA damage response and cell death,” according to John Perry, the study’s senior author and a geneticist and professor at the Wellcome-MRC Institute of Metabolic Science at the University of Cambridge. “There’s currently no well-understood biological paradigm for how DNA damage response would influence body size. These findings have given us a signpost to suggest variation in this important biological process may play a role in the etiology of obesity.”
Their analysis linked rare loss-of-function variants in three genes—DIDO1, PTPRG, and SLC12A5—with higher BMI in adult women but not adult men. Faulty variants of another gene, SLTM, showed a similar result in men. Specifically, more than 80% of women with DIDO1 and SLC12A5 variants had obesity. Also, DIDO1 variants were associated with higher testosterone levels and greater waist-to-hip ratio—both risk factors for obesity-related maladies like diabetes and heart disease. The study also showed that women with SLC12A5 variants were at greater risk of developing type 2 diabetes.
The age-based analysis highlighted several genes associated with childhood obesity and higher adult BMI including MC4R and CALCR. It also revealed two genes—OBSCN and MADD—that were not previously associated with childhood body size. Furthermore, members of the population that had OBSCN variants were more likely to have weighed more as children. People with MADD variants, on the other hand, had smaller body sizes as children and were not likely to be obese adults.
“We’re at the very earliest stages of identifying interesting biology,” Perry said. “We hope the study can reveal new biological pathways that may one day pave the way to new drug discovery for obesity.” As part of their next steps, the research team plans to replicate the study in a larger, more diverse human population. They also plan to study relationships between genes and obesity in animals.
