New Insights into Severe Obesity Genetics: Evidence from Adults Seeking Treatment Reveals Intriguing Oligogenic Patterns

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Obesity is a complex disorder that is dependent on environmental and genetic factors. Severe obesity, which is otherwise known as class III obesity, is a chronic condition that increases the risk of mortality and morbidity.

Current estimates indicate that the healthcare costs of individuals with severe obesity are 40% greater as compared to people with normal weight. Therefore, it is important to understand the etiology of class III obesity.

Study: Severe obesity may be an oligogenic condition: evidence from 1,714 adults seeking treatment in the UK National Health Service. Image Credit: Fuss Sergey /

*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.


Genetic research has revealed that several common genes have a subtle influence on body mass index (BMI) or increase the risk of obesity. Although a monogenic form of obesity has been identified, it is a rare occurrence in the general population; however, its frequency may be greater in a clinically obese cohort.

As compared to adults, a greater amount of research has been dedicated to understanding the complexities of severe forms of childhood obesity. As a result, limited precision medicine approaches have been developed to treat adults with class III obesity.

Although the effect of oligogenic inheritance has been established for many diseases, there is a lack of evidence regarding its influence on severe obesity.

About the study

A recent study posted to the medRxiv preprint server explores the prevalence of rare genetic forms of obesity in a United Kingdom-based clinical obesity cohort. A custom-designed rare-variant genotyping array was developed to determine genes related to Mendelian forms of obesity and diabetes. 

For this study, 27 genes that clinically indicate severe early-onset obesity were considered, in addition to 51 genes linked to syndromic and non-syndromic obesity. All genetic variants present in the Human Gene Mutation Database (HGMD) for each of the selected genes were selected, irrespective of their phenotypes or pathogenicity levels.

The newly developed genotyping array was applied to 1,714 unrelated adults seeking treatment for severe obesity. These participants were recruited between 2011 and 2021 for the Personalised Medicine for Morbid Obesity (PMMO) National Health Service (NHS)-registered portfolio trial. The results of the genetic screen were compared with the clinical cohort containing 50,000 whole exome sequencing (WES) datasets from the U.K. Biobank.

Study findings

An optimized algorithm was used to determine the prevalence of genetic variants that potentially cause Mendelian forms of obesity in the U.K.-based obesity cohort. Notably, one in every twelve PMMO participants had rare variants in genes that clinically indicated severe childhood obesity. This estimation increased to one in four participants when gene variants were included.

Since severe adult obesity is a relatively unexplored area of research, standard clinical genetic measures could not be employed to “prune” mutations for inclusion criteria. About 10% of the included genetic variants were classified as variants of uncertain significance (VUS).

As compared to previous studies, the current study observed a higher prevalence of possible Mendelian obesity. This disparity in results could be due to other studies considering variants from fewer genes.

When variants assigned to genes from an NHS panel used for clinical indication of severe early-onset obesity were considered, the current study estimates of 8.6% resembled findings documented in previous studies. 

Consistent with previous findings, the current study estimated that 0.88% of PMMO participants carried at least one rare variant in the MC4R gene. In the PMMO cohort, two participants carried both the MYT1L and GHSR genes. Future research must explore whether these two genes interact with each other to influence obesity risk.

The findings of the custom-designed rare-variant genotyping array were compared with the WES dataset of the UKB cohort, which revealed that the overall prevalence of qualifying variants was not significantly different. This finding was surprising, as the UKB cohort represented healthy individuals. 

Strengths and limitations

One of the key strengths of this study was the utilization of PMMO, which is based on an extreme phenotype of class III obesity. As a result, the frequency of rare genetic variants linked to severe obesity that cause Mendelian forms of obesity could be accurately determined. 

Although the newly developed genotyping methodology is cost-effective and time-efficient, it is associated with some limitations. For example, this approach cannot identify any novel variants linked to class III obesity, as it can only analyze variants present in the Genome Aggregation Database (gnomAD) or HGMD. Due to limited research in this field, the pathogenicity of many variants included in the array is not fully understood. 


PMMO participants with a putatively Mendelian form of obesity were more likely to carry predicted-deleterious mutations in more than one gene than U.K. Biobank participants. The study findings emphasize the role of oligogenic inheritance in severe obesity and the importance of genotyping arrays for rare variant screening.

*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

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