Genome-wide association study provides novel insight into the genetic architecture of severe obesity

Severe obesity (SevO) is a primary driver of cardiovascular diseases (CVD), cardiometabolic diseases (CMD) and several cancers, with a disproportionate impact on marginalized populations. SevO is an understudied global health disease, limiting knowledge about its mechanisms and impacts. In genome-wide association study (GWAS) meta-analyses of the tail end of the BMI distribution (≥95th percentile BMI) and two SevO phenotypes [Obesity Class III BMI ≥ 40 kg/m2 and Obesity Class IV BMI ≥ 50 kg/m2] in 159,359 individuals across eleven ancestrally diverse population-based studies followed by replication in 480,897 individuals across six ancestrally diverse studies, we identified and replicated three novel signals in known loci of BMI [TENM2, PLCL2, ZNF184], associated with SevO traits. We confirmed a large overlap in the genetic architecture of continuous BMI and severe obesity phenotypes, suggesting little genetic heterogeneity in common variants, between obesity subgroups. Systematic analyses combining functional mapping, polygenic risk scores (PRS), phenome wide association studies (PheWAS) and environmental risk factors further reinforce shared downstream comorbidities associated with continuous measures of BMI and the importance of known lifestyle factors in interaction with genetic predisposition to SevO. Our study expands the number of SevO signals, demonstrates a strong overlap in the genetic architecture of SevO and BMI and reveals a remarkable impact of SevO on the clinical phenome, affording new opportunities for clinical prevention and mechanistic insights.Author summary: Severe obesity (SevO), which includes individuals with a body mass index (BMI) over 40 kg/m2, is a major cause of heart disease, diabetes, and some cancers. It affects marginalized communities at higher rates but remains under-researched. To better understand the biology behind severe obesity, researchers analyzed genetic data from over 159,000 people of diverse backgrounds and confirmed their findings in nearly 481,000 more individuals. The study identified three new genetic regions linked to severe obesity, within genes already known to influence body weight. Interestingly, the study showed that severe obesity and overall BMI share much of the same genetic background, meaning the genes that influence body weight also contribute to more extreme obesity. By combining genetic risk scores, health records, and environmental factors, the research highlighted how genetic predisposition and lifestyle together shape the risk for severe obesity and related health problems. This work expands our knowledge of the genetic factors behind severe obesity and emphasizes the importance of both genetics and the environment in tackling obesity-related diseases, offering new insights for prevention and treatment.