Several genes associated with obesity in women, as well as two in men, were uncovered in a large-scale study using U.K. Biobank data carried out by researchers from Cambridge University. These findings highlight the importance of considering sex-specific aspects in the genetics of obesity.
“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,” the researchers write.
Their study was published in Cell Genomics. The lead author is Lena R. Kaisinger of the MRC Epidemiology Unit, Wellcome-MRC Institute of Metabolic Science at University of Cambridge in U.K.
According to the World Health Organization, obesity is a global problem, affecting an estimated two billion adults.
In this study, the genes linked to obesity in women were DIDO1, KIAA1109, MC4R, PTPRG, and SLC12A5. Those linked to the condition in men were MC4R and SLTM. MC4R has previously been linked to both male and female obesity. DIDO1, MADD, and SLTM have also been tied to cell death and DNA damage.
Large-scale exome sequencing studies have identified several genes in which variants have large effects on adult body mass index (BMI). But as these researchers write, “Sex-specific associations with body size and metabolic disease have been described for common genetic variation, yet few examples exist for rarer variants, which offer greater opportunity to directly implicate causal genes. Likewise, common variant genome-wide association studies (GWASs) have been performed for recalled childhood adiposity, yet no similar study exists for rarer variants.”
This study looked at sex-stratified associations in the U.K. Biobank study (N∼420,000). They looked for rare coding variants with sex-specific effects on adult BMI, or associated with childhood adiposity. They relied on adults/ subjectively recalled history of childhood body adiposity (sample size ∼400K).
This team found that more than 80% of women with DIDO1 and SLC12A5 variants had obesity, and those with the DIDO1 mutant also had higher testosterone levels and a greater waist-to-hip ratio. Both of which indicate risk for obesity-related diabetes and heart disease. Women with the SLC12A5 variant also had a higher rate of type 2 diabetes, when compared to women without it.
The researchers note that, “Rare protein-coding variants in the remaining three genes, identified for BMI in females (DIDO1, PTPRG, and SLC12A5), have not previously been implicated in adiposity and appear to have female-specific effects.”
Two of the genes, MC4R and KIAA1109, were reported in previous sex-combined ExWAS for BMI, and showed exome-wide significant or subthreshold associations with BMI in both sexes, as did SLTM.