A study has identified genes that influence obesity risk across gender and age groups, providing new insights into the biological pathways of obesity. These findings highlight the importance of considering sex and age in obesity research and may lead to new treatments. Researchers have identified genes that affect obesity risk differently in men and women and across age groups, revealing potential new ways to understand and treat obesity.
From influencing how the body stores fat to how the brain regulates appetite, hundreds of genes and environmental factors combine to determine our weight and shape. Now, researchers have added several more genes to that list that appear to influence obesity risk in certain genders and ages. The study, published in the journal Cell Genomics, may reveal new biological pathways that lead to obesity and highlight how gender and age influence health and disease.
"There are countless reasons why we should consider sex, age and other specific mechanisms, rather than lumping everyone together and assuming disease mechanisms work the same way for everyone," said geneticist John Perry, senior author and professor at the Wellcome-MRC Institute of Metabolic Sciences at the University of Cambridge, UK. "We don't expect people to have completely different biology, but you can imagine that there are hormonal and physiological factors that may contribute to specific risks."
To unravel the role of sex in obesity risk, the team sequenced the exomes (the protein-coding parts of the genome) of 414,032 adults in the UK Biobank study. They looked at genetic variants, or mutations, associated with body mass index (BMI) in men and women separately. Body mass index is an estimate of obesity based on height and weight. The search revealed five genes that affect body mass index in women and two that affect body mass index in men.
Of these, faulty variants in three genes - DIDO1, PTPRG and SLC12A5 - were associated with higher body mass index in women, up to nearly 8kg/m2, but had no effect in men. More than 80% of women carrying the DIDO1 and SLC12A5 variants are estimated to be obese based on body mass index (BMI) estimates. People who carry the DIDO1 variant are more closely associated with elevated testosterone levels and an increased waist-to-hip ratio, both of which are risk indicators for obesity-related complications such as diabetes and heart disease. People who carry other SLC12A5 variants have a higher chance of developing type 2 diabetes than non-carriers. The findings highlight previously unexplored genes that are associated with the development of obesity in women but not men.
Perry and his colleagues then repeated their approach, looking for age-specific factors by looking for genetic variants linked to childhood body size based on participants' recollections. They discovered two genes, OBSCN and MADD, that had not previously been linked to body size and fatness in childhood. Carriers of the OBSCN variant are more likely to be heavier as children, while carriers of the MADD variant are smaller. Furthermore, genetic variants acting on MADD were not associated with adult obesity risk, highlighting age-specific effects on body size.
"Surprisingly, if you look at the function of some of the genes we found, several genes are clearly involved in the DNA damage response and cell death," Perry said. "Obesity is a brain-related disease, and biological and environmental factors can influence appetite. There is not yet a well-understood biological paradigm for how the DNA damage response affects body size. These findings provide us with a signpost that variations in this important biological process may play a role in the etiology of obesity."
Next, the team hopes to repeat the study in a larger and more diverse group of people. They also plan to study these genes in animals to understand their function and relationship to obesity.
"We are in the early stages of identifying the interesting biology," Perry said. "We hope this research will reveal new biological pathways that may one day pave the way for the discovery of new drugs for obesity."