Obesity is a significant health problem, and its prevalence has increased substantially in the last decades, with a global burden of around 2 billion people in the latest reports. Most notably, body mass index (BMI) is a strongly heritable phenotype, with heritability estimates reaching over 80% for high BMI. Therefore, we intend to discover new monogenic obesity genes and also better delineate the genomic landscape of obesity using innovative approaches. Our group leverages the Turkish Obesity Study database, which now consists of 4,626 whole exome and 830 whole genome sequenced individuals from ~800 families. In addition to detailed pedigree information, there is robust clinical phenotyping and an accompanying database. We have identified homozygous and heterozygous variants that reach genome-wide significance in genes not previously associated with obesity. We have also identified novel variants in known obesity-related genes (LEP, LEPR, MC4R, PCSK, POMC, ADYC3, and BBS2). We now intend to advance our investigations by including UK Biobank data.
We aim to:
1. Discover new monogenic obesity genes.
2. Discover phenotypic traits of the monoallelic forms of recessive monogenic obesity genes.
3. Identify cumulative effects on BMI of low penetrance monogenic obesity genes.
This approach constitutes the scientific rationale of the proposed research project. The research is expected to:
1. Increase our understanding of the genomic landscape of obesity and associate new genes with high BMI, potentially presenting new targets for drug development.
2. Better delineating the contribution of known genes to obesity phenotype expands the scope of well-established treatments.
3. Potentially explain phenotypical variances in obesity, including endophenotypes.
4. Address the status of heterozygotes for pathogenic variants in biallelic genes concerning specific health outcomes in the domain of complex diseases, for example, age of onset, milder or a different phenotype.
We expect this project to be completed in 36 months.