Genes Predisposing to Monogenic, Polygenic, and Syndromic Obesity: A Review of Current Trends and Prospects for Standard Obesity Genetic Testing

Objective: The burden of obesity is currently enormous, necessitating a novel strategy to complement the existing ones. Accordingly, genetic predisposition is suspected in many cases of the disease, which can potentially be used as therapeutic targets. However, there are differing viewpoints on the suspect genes, prompting the current review to articulate the genes and their mechanisms. Eight (16%) of the genes singularly predispose humans to obesity (called monogenic obesity), 22 (43%) interact with other genes and the environment to predispose humans to obesity (called polygenic obesity), and 21 (41%) cause syndromic obesity. Monogenic obesity is often caused by three genes [the leptin ( LEP ), the leptin receptor ( LEPR ), and the melanocortin 4 receptor ( MC4R ) genes], polygenic obesity [fat mass and obesity-associated ( FTO ) gene], and syndromic obesity (Prader-Willi Syndrome). These genes control food intake and energy expenditure, and so mutations in them cause overeating, adiposity, and hyperphagia. Based on these findings, two genetically-based drugs, named recombinant human leptin and setmelanotide, have been formulated and shown to significantly reduce food intake, body weight, and fat mass. This suggests that when the genetic etiology of obesity is fully understood, the disease’s treatment and prevention will improve. Healthcare providers are urged to develop genetically-based personalized treatments for obese patients.


Introduction
besity is described as excessive fat accumulation that is harmful to health (1,2). There is no perfect method for measuring obesity. However, the most commonly utilized methods are body mass index (BMI) and waist circumference (3,4). The BMI of a person is computed by multiplying the weight in kilograms by the height in meters squared (5). A BMI of 25 or more is considered overweight, whereas a BMI of 30 or above is considered obese (6,7). Waist circumference is a less common method for determining obesity in adults, which involves measuring the waist (8). Females with a waist circumference of 80 cm or more are regarded as unhealthy, while males with a waist circumference of 94 cm or more are deemed unhealthy (9,10).
Obesity and overweight prevalence have skyrocketed in recent years, reaching epidemic proportions with the incidence rate more than doubling since 1980 (11). Obesity was thought to be an issue only in advanced countries, but it is currently highly prevalent in developing countries, particularly in urban areas (12). This is a consequence of industrialization and economic globalization, which have aided the spread of obesogenic products (calorie-laden western diets) such as sugar-sweetened beverages and packaged foods to developing countries (13). As of 2016, about 44% of adults (more than 2 billion) worldwide were overweight or obese, with over 70% of them living in low-or middle-income nations. This information debunks the belief that obesity is only a problem in high-income countries (14).
Overweight and obesity affect about 30% and 10% of adults in Sub-Saharan Africa, respectively (15). In Nigeria, approximately 21 million and 12 million people aged 15 and above were overweight or obese in 2020, accounting for a 20.3% and 11.6% ageadjusted prevalence, respectively (16).
Obesity and being overweight can cause several potentially fatal illnesses (17). The most prevalent of these illnesses include high cholesterol, high blood pressure, heart disease, diabetes mellitus, gallbladder disease, stroke, osteoarthritis, sleep apnea, respiratory problems, and cancers (17,18). Obesity can also cause dyslipidemia, non-alcoholic fatty liver disease (NAFLD), lower quality of life, psychosocial problems, and a shorter lifespan (19). Over 2.8 million people die each year from the mentioned diseases and other obesity-related disorders (2). Obesity was responsible for around 4 million fatalities in 195 countries in 2015, the majority of which were due to cardiovascular complications (20). In advanced countries, obesity and its accompanying chronic conditions, such as diabetes, cardiovascular disease, and cancer, lower life expectancy by an average of 2.7 years (21).
Aside from the health burden, the increasing prevalence of obesity is also causing a huge threat to economies worldwide. The rise in weight-and obesity-related disorders has not only harmed the health of billions of people, but has also resulted in enormous economic costs. Obese people miss more days of work than people who are not obese, and they operate at a lower capacity while they are at work (22). Obesity also raises the risk of being laid off and has a negative influence on income (22). In many developed nations, 8.4% of the health budget is spent on treating the consequences of being overweight (21). Obesity reduces GDP by 3.3% on average in many developed countries (21). In Nigeria, there is a scarcity of data on the cost of healthcare services for obese people. However, a clinical study showed that obese Nigerians spend more money on medical treatments than non-obese Nigerians (23,24).
Available treatment options for obesity include lifestyle and diet adjustment, regular exercise, weight loss, medication, and surgery (25) epigenetic, environmental factors, and lifestyle are suspected of the disease's rising burden. Genetic factors, in particular, account for about 40-70% of the incidence, and many candidate genes have been identified (26). However, the list of suspect genes is growing. This study was conceived to provide current information on the identified genes and their obesogenic pathophysiology. This will aid healthcare providers in making accurate diagnoses and developing appropriate therapies for those who are affected.

Pathogenesis of obesity
The first law of thermodynamics, when applied to body weight, states that body weight will remain unchanged if energy intake and expenditure are equal during a given time period. So, overweight or obesity is caused by overeating or poor energy expenditure (27,28). The body is in energy equilibrium when energy intake matches energy expenditure and body energy (often equivalent to body weight) is stable (27,29). In healthy individuals, adipose tissues play a critical role in maintaining this equilibrium at both the organ and systemic levels (30). White adipose tissue stores excess energy as a lipid and regulates lipid mobilization and distribution in the body (30). It does this by recruiting more adipocytes to accumulate more fat and undergo cellular hypertrophy. White adipose tissue also functions as an endocrine organ and produces several bioactive substances such as adipokines, which communicate with other organs to regulate several metabolic pathways (30). Brown and beige adipose tissues, on the other hand, burn lipid by dissipating energy in the form of heat during a calorie shortfall (30). Adipose tissues, along with the pancreas and digestive tract, send signals to the central nervous system, which help regulate appetite and thus calorie intake and energy expenditure (31). Obesity, on the other hand, reduces adipose tissue storage capacity, resulting in energy imbalance and fat buildup in visceral adipose depots as well as ectopic tissues such as the liver, skeletal muscle, and heart (30,32).
Small deviations from the homeostatic mechanisms, as low as less than 2% of daily energy intake, can cause significant long-term changes in body weight (~20 kg) (31,33). To sum it up, when energy intake exceeds energy expenditure, body fat mass (of which 60 to 80% is usually body fat) increases, while it decreases when energy expenditure exceeds intake (27,34). Factors that modulate the association between dietary intake and obesity include physical activity, genetic and epigenetic factors, chemical or pollutant exposure, poor sleep pattern, microbiota, energy-dense diets, over-nutrition, and adipose tissue dysfunction (30,33,34). These factors disrupt either energy intake, expenditure, storage, or all (27).

Genetic basis of obesity
The brain employs the signals sent into the central nervous system by adipose tissues, the pancreas, and the digestive tract to instruct the body on its energy needs (35,36). These signals are transmitted by hormones such as insulin, ghrelin, leptin, and some molecules, all of which are coded for by genes. Thus, any changes in these genes can affect their expressions and functions (35). This underscores the importance of genes in energy homeostasis, obesity pathogenesis, prevention, and treatment. To this end, studies have demonstrated that genetic predisposition contributes to about 40-70% of cases of obesity, and so far, over 50 genes are strongly linked with the disease (25,37). Some of these genes alone predispose people to obesity (referred to as monogenic obesity), whereas others combine with others and the environment to predispose people to obesity (referred to as polygenic obesity) (38,39). There is also syndromic obesity, which is severe obesity associated with phenotypes such as neurodevelopmental and organ abnormalities (38,39). Monogenic causes are primarily involved in signal transmission and embedded mainly in the hypothalamic leptin/melanocortin axis, while the polygenic interacts with the environment (38,39). 251 Polygenic causes are the most prevalent in the obese population, while monogenic causes account for just about 5% (38). The most frequent causes of monogenic obesity are mutations in leptin (LEP), the leptin receptor (LEPR), and the melanocortin 4 receptor (MC4R) genes (40). The fat mass and obesityassociated gene (FTO) is the commonest causes of polygenic obesity and, by extension, the commonest causes of obesity, found in up to 43% of the obese (35). Prader-Willi Syndrome (PWS) is the commonest cause of syndromic obesity and is found in 1 in 15,000-25,000 births (39,41).
The current review identified over 100 obesity candidate genes. However, some were not replicated in follow-up studies, so only 51 genes that were regularly linked with the disease were included in this study. Of the 50 genes, 8 (16%) cause monogenic obesity, 22 (43%) cause polygenic obesity and 21 (41%) cause syndromic obesity.

Genetic testing for obesity: progress, benefits, and costs
There is no standard genetic testing panel for obesity yet. Some hospitals, laboratories, research institutions, and pharmaceutical corporations, however, sequence well-known candidate genes in order to find the functional mutation that may be causing a patient's body weight gain (159). Some of these laboratories and companies include Sequencing.com, 23andMe, Dante Labs, AncestryDNA, and MyHeritage (160). These laboratories often sequence the cheek swab of the affected person using whole-genome sequencing (160). DNA test kits are also available from the companies.
The results of the DNA test are being used in weight-loss programs. Some people approach a nutritionist or licensed dietitian to develop a personalized nutrition plan based on their test results (160). Obesity genetic testing has helped reduce some of the burdens of the disease, which includes feelings of shame by patients and stigmatization by the public. Importantly, the test results are being used to personalize treatment for individual patients. Currently, two such personalized and genetically-based drugs have been produced and approved, and they are recombinant human leptin and setmelanotide (159,161). Leptin replacement therapy has been found to help patients who are lacking in leptin caused by LEP gene mutations (159,161). Setmelanotide is a selective MC4R agonist that helps patients with POMC, PCSK1, or LEPR deficiency compensate for the lack of melanocyte-stimulating hormone (MSH) (159,162). A daily dermal injection of setmelanotide significantly decreased weight and hunger (159). However, setmelanotide has minor adverse effects, which include nausea, hyperpigmentation, vomiting, darkening of skin, injection site reactions, and penile erections (159,162). Generally, testing for obesity genes early in life, especially for those with a family history of obesity, has been demonstrated to be beneficial as it allows affected individuals to plan their diet ahead of time and lower their risk of becoming obese (26,163). If a large number of obese people get access to this facility, the disease's incidence and burden will undoubtedly decrease.
In recent years, the cost of genetic testing for various diseases has been reduced, unlike in the past when the human genome was first sequenced. According to Medline Plus (164), the cost of genetic testing in the United States ranges from below $100 to over $2,000. The costs are higher if several tests are required or several members of the family need to be tested before a meaningful result can be obtained. The cost of genetic screening for newborns depends on the state. Some states pay some of the costs, but most tests cost between $30 and $150 per infant. The decreasing cost has made genetic testing more accessible to millions of people around the world (160). This has definitely had a positive impact on the cost of obesity genetic testing. Some laboratories, like sequencing.com and personal diagnostics, sell obesity DNA test kits for between $69 and £39.98 (160,165 "Rhythm" even offers a free genetic testing program for patients (166). When these costs are compared with the attendant obesity burden reduction that follows genetic testing, the cost is worthwhile. With the current trend, the costs are likely to be reduced further. With increasing knowledge, a standard obesity genetic panel could be developed, making testing more affordable and effective. However, poverty and a lack of facilities, proper planning, and information may hinder the progress of developing nations.

Conclusion
Mutations in the genes that control food intake and energy expenditure may cause overeating, adiposity, and hyperphagia, resulting in overweight or obesity. These genes accounted for between 40 and 70% of cases of obesity. Given the huge contribution of genetics to the incidence of obesity, treatments tailored to the causal genes and their pathophysiology in affected individuals will significantly improve the condition. To this end, two genetically-informed drugs, named recombinant human leptin and setmelanotide, have been formulated and found to be effective. As such, healthcare providers are encouraged to design drugs and treatments based on the pathophysiology of the causal genes in the affected individuals. The strength of this study lies in its ability to articulate genes and variants based on the types of obesity they cause, which may aid in effective diagnosis and treatment procedures. The weakness of the study lies in its inability to take into account the prevalent obesity genes in each region of the world, among ethnic groups, and genders. This weakness is a pointer for future study. (49,50)

POMC/ Tyr221Cys
Proopiomelan ocortin 2p23.3 It produces several peptides, one of which is beta-melanocyte stimulating hormone, which regulates weight by binding to the MC4R receptor. The brain's signaling through this receptor serves to maintain the balance between the energy consumed by the body and the energy expended by the body.
It causes proopiomelanocortin insufficiency, which is characterized by a lack of α-MSH and β-MSH-mediated signaling in the brain, causing the body's energy balance to be disrupted, resulting in overeating and severe obesity.

ANK2/R1788W and L1622I
Ankyrin 2 4q25-q26 The ANK2 gene produces ankyrin-B, a protein that helps organize the cell's structural framework (cytoskeleton) and connects some proteins that traverse the cell membrane to the framework. Ankyrins also play a role in cell movement (migration) and cell growth and division (proliferation).
Causes increased glucose intake by fat cells, which results in increased weight and culminates in obesity when the metabolism ages or a high-fat diet is eaten. This eventually results in the spilling of lipids in the fat cells onto the liver and muscles, causing inflammation in the tissues and insulin resistance, a hallmark of type II diabetes.

RBMX/p.V170 I and p.R647C
RNA binding motif protein X-linked Xq26.3 RBMX is necessary for the normal development of the brain.
It results in Shashi-X-linked mental retardation, which is characterized by mild intellectual retardation, obesity, and macroorchidism.