Genome wide association studies based within specific population groups provide an excellent opportunity for pinpointing rare and high impact genomic variants in already well studied traits, such as body-mass index (BMI).
We performed an exploratory GWAS in Estonian biobank (EstBB) to describe BMI-affecting variants (189,538 participants). Our analysis identified 178 significant loci, of which a majority have previously been reported to associate with obesity-related traits. To pinpoint functionally relevant SNVs, we characterized individual variants by their consequence on protein-coding genes, in correlation to CADD score and beta coefficient.
Among the most significant functional hits, a stop-gain variant rs202127120 (POMC:Glu206X) within the pro-opiomelanocortin (POMC) gene, was identified. Using Sanger sequencing, we confirmed this variant to be present within 0.87% of biobank participants (n=1,740), displaying to our knowledge a considerably higher allele frequency in Estonia than in other global populations. The POMC:Glu206X variant results in an early truncation of the POMC precursor polypeptide and results in lower β-MSH and β-endorphin levels in the hypothalamic-pituitary-adrenal axis, thus resulting in an inadequate leptin-melanocortin pathway triggering.
POMC:Glu206X variant carriers display significantly higher BMI among all biobank participants (+0.85 kg/m2; p=9.2x10-13), higher overall weight (+2.70 kg; p=3.8x10-13), waist circumference (+1.69cm; p=1.9x10-5) and higher BMI among 18-39 year old participants (+1.008 kg/m2; p=1.5x10-8). A PheWAS utilizing electronic health records confirmed the enrichment of obesity related diagnoses among the POMC:Glu206X variant carriers (Top hit: “Overweight and obesity”, OR=1.42, p=8.3x10-5).
In this currently ongoing work, we identified a remarkably prevalent stop-gain variant in POMC gene, which previously has been considered highly deleterious. We demonstrate that POMC:Glu206X significantly associates with risk of obesity. We will next be proposing clinical intervention trials to ameliorate the effect POMC:Glu206X has on the local population. Furthermore, this bioinformatic approach will further be applied on thousands of other GWAS summary statistics available within the Estonian biobank, thus potentially yielding in the discovery additional novel biologically and clinically relevant variants.