As an Obesity specialist and endocrinologist, I often hear patients say, I have tried every diet that is available in the world, but nothing works or Obesity runs in my family. But you know what? They are not entirely wrong.
Obesity isn’t just about calories in versus calories out. While lifestyle is key, genetics play a powerful role, sometimes tipping the scale long before a person picks up a fork. Today, I want to walk you through the genetics of obesity, focusing on monogenic causes and the increasingly important role of polygenic risk scores.
Let’s begin with monogenic obesity. This is a rare form, but severe and often starts in early childhood. It’s caused by mutations in a single gene that plays a crucial role in energy balance like MCR4, LEP or LERP genes.
These genes are part of a network in the hypothalamus, the brain’s control centre for hunger and satiety. When one of these genes malfunctions, it disrupts the feedback system that normally tells us when we are full. The result? Constant hunger and rapid weight gain.
While rare, these cases are eye-opening because they show just how deeply biology can override willpower. In some patients, medications like setmelanotide, which target these specific pathways, are changing lives.
On the other hand, polygenic obesity is far more common. Here, no single gene is to blame. Instead, it’s a combination of hundreds or even thousands of genetic variants, each nudging your risk a little higher.
These variants, often identified through genome-wide association studies, are involved in a range of processes: fat storage, appetite, metabolism, and even food preferences. One of the most studied genes is FTO. Variants here can increase appetite and reduce satiety signals.
We use something called a polygenic risk score to estimate a person’s inherited risk. The higher the score, the more likely they are to gain weight, especially in today’s high-calorie environment. Think of it as genetic sensitivity to modern life.
A study analysed over 2.1 million single-nucleotide polymorphisms (SNPs) from the UK Biobank to develop a PRS that could predict BMI variations. While the PRS showed strong associations with BMI and obesity, its predictive performance remains modest, explaining up to 23% of BMI variation.
Importantly, lifestyle factors can modulate genetic risk. A cohort study involving 3,124 adults found that individuals at high genetic risk of obesity needed to engage in more physical activity to offset their predisposition. Specifically, those in the 75th percentile of PRS required an average of 2.280 additional steps per day to maintain a similar obesity risk as those in the 50th percentile.
This finding emphasises that while genetics plays a significant role in obesity risk, lifestyle interventions remain a critical component of prevention and management strategies.
Beyond genetic variants, epigenetic modifications are heritable changes in gene expression without alterations in the DNA sequence that also contribute to obesity. Epigenome-wide association studies have identified methylation sites associated with obesity-related traits, offering potential targets for intervention.
Additionally, recent research has explored the connection between genetic factors and brain function in obesity, suggesting that certain genetic determinants may influence neurodevelopmental and mental health aspects related to obesity.
Genetics plays a significant role in obesity, both through rare single-gene disorders and through a mosaic of common variants. But lifestyle choices, epigenetics, and even mental health all influence how these genes show up in our lives.
Understanding whether a person’s obesity has a monogenic cause or polygenic background can change the treatment plan. It helps us move away from blame and toward tailored, compassionate interventions, whether that’s medication, behavioural support, or early preventive strategies in high-risk individuals.
Genetic testing isn’t about labelling people. It’s about unlocking tools for precision medicine and giving patients answers when they have been struggling in silence.
Kripa, is a Specialist Dietitian at The London Obesity & Endocrine Clinic. She has helped many patients overcome weight management barriers. ©Simplyweight
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