The study of rare variants in new genes related to obesity in an Iranian population

More than 1 billion people worldwide live with obesity, a rapidly increasing global health challenge. Obesity is the second leading preventable cause of death, increasing the risk of diseases such as type 2 diabetes (T2D), cardiovascular disease and cancer. Understanding the broad range of social, psychological and biological factors that determine energy intake and expenditure will be key to addressing this challenge. Early studies in mice highlighted the role of the leptin-melanocortin pathway in regulating appetite and body weight, leading to candidate gene sequencing studies in individuals with severe early-onset obesity. These studies identified rare loss-of-function mutations in key components of this pathway as causes of early-onset obesity. The most common of these affect MC4R. In parallel, using a “hypothesis-free” approach, genome-wide association studies (GWAS) have identified hundreds of common genetic variants associated with body mass index (BMI) in adults. These variants are mostly noncoding and cluster close to genes expressed in the brain. Individually, the effect of each variant is small, and collectively, the approximately 1000 common variants identified to date explain only about 6% of the population variance in BMI. The recent advent of population-scale whole exome sequencing (WES) data has enabled exome wide association studies (ExWAS), which have led to the convergence of discoveries of common and rare variants. In a landmark study, Akbari et al. used WES data from 640,000 individuals to identify rare protein-coding variants in 16 genes associated with BMI. These included genes with proven roles in weight regulation, including MC4R, GIPR, and PCSK1, in addition to novel targets, such as GPR75, in which loss-of-function mutations protect against obesity in humans and mice. Another ExWAS study for BMI using WES data from 419,668 individuals in the UK biobank identified novel rare variants associated with the BSN and APBA1 genes, which were replicated in independent WES data from 167,359 individuals of predominantly non-European genetic ancestry. These rare protein truncating variants (PTVs) have larger effects than other previously reported ExWAS genes, and the findings of this study collectively suggest emerging roles for neural development, neurogenesis, and altered neuronal oxidative phosphorylation in the etiology of obesity. In this project, the goal is to use WES data from individuals with early-onset severe obesity and identify variants of genes proven to be involved in obesity, as well as specifically novel variants of the BSN and APBA1 genes in these individuals, and then to examine the genomic sequences of individuals with severe obesity for these variants through the Sanger confirmation method to prove the association of obesity with the gene variant of interest in individuals with severe obesity in the Iranian population.