Faulty variants of three genes have been linked to obesity-related conditions, while having no effect on men, shedding light on new biological pathways underlying obesity, according to a new study.
“There are a million and one reasons why we should be thinking about sex, age, and other specific mechanisms rather than just lumping everyone together and assuming that disease mechanism works the same way for everyone,” said senior author John Perry, a geneticist and professor at the University of Cambridge, UK.
The research team sequenced the exome – protein-coding part of the genome – of more than 4,14,000 adults from the UK Biobank study and looked at variants, or mutations, within genes associated with body mass index (BMI) in men and women, respectively. They have published their findings in the journal Cell Genomics.
Defective variants of three genes – DIDO1, PTPRG, and SLC12A5 – were linked to higher BMI in women, while having no effect on men.
While women carrying DIDO1 variants had stronger associations with higher testosterone levels and increased waist-to-hip ratio, both being risk indicators for obesity-related complications like diabetes and heart disease, those with SLC12A5 variants were found to have higher odds of having type 2 diabetes.
Perry and the team then repeated the process looking for age-specific factors influencing obesity. They searched for gene variants associated with childhood body size based on participants’ recollections.
They identified two genes, OBSCN and MADD, previously not linked to childhood body size and fat.
While carriers of OBSCN variants had higher odds of having higher weight as a child, MADD variant carriers were associated with smaller body sizes, the researchers said.
Further, the genetic variants acting on MADD were found to have no association with adult obesity risk, highlighting age-specific effects on body size.
“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,” said Perry.
“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 aetiology of obesity,” said Perry.
Next, the research team hopes to replicate the study in a larger and more diverse population.
“We hope the study can reveal new biological pathways that may one day pave the way to new drug discovery for obesity,” said Perry.
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