Monogenic, Oligogenic, and Polygenic... what's the difference?

Series Overview: Hi, my name is Shari and like the majority of our readers I don’t have a degree in science. What I do have is almost a decade of experience working closely with Genetic Counselors, and a passion for sharing genomic information in an approachable and easy to understand way. This passion was developed early in my career, fueled by my quickly building frustration about the over-complicated resources I found during initial attempts at self-guided learning. Genomics 101 is a blog series by GenomicMD that aims to be a solution to that frustration for others. By breaking down the complex language surrounding this field, we hope to empower people (like you!) to be more informed about how genomics can affect their healthcare journey.

Welcome back to Genomics 101, the blog series where we break the fascinating (but often overwhelming) field of genetics down into language that is easy to understand. Our last few lessons have focused on building a foundational knowledge of heredity - both the history of its discovery and its scientific meaning. To recap some of our most recent posts - we have discussed the difference between the terms "genetics" and "genomics," reviewed different types of ancestry, and explained the role genetic recombination plays in determining which traits are passed down the family line. Previously, we also defined terms such as variants and alleles, examined how some traits are inherited in either a dominant or recessive pattern, and explored how these patterns as well as a given variant’s penetrance can affect the expression of these traits in future generations. Today’s lesson will add additional context to this discussion by examining the 3 main ways traits are defined: Monogenic, Oligogenic, and Polygenic. 

Let’s start with the earliest discovered inheritance type and a concept that is pretty straightforward: monogenic inheritance. The term monogenic refers to any trait (in healthcare, usually a genetic condition or disease) that is caused by a variant or mutation within only one gene - also called “single gene inheritance”. When referring to disease, those caused by monogenic inheritance tend to be both rare and significantly impactful, such as Huntington’s Disease. There are several basic patterns to note when discussing the inheritance of monogenic traits, but we have already defined two in previous posts: autosomal dominant and autosomal recessive. Traits caused by changes in a single gene are most often inherited in a very straightforward pattern like these, as observed by Gregor Mendel during his early experiments with pea plants. This is why this type of inheritance is also sometimes referred to as “Mendelian inheritance.” Although rare, conditions caused by this type of inheritance are usually easy to test for due to their simple patterns. Think about it - knowing that a specific variant, in a specific place, inherited in a specific way will ALWAYS cause a specific thing to happen would probably make that thing a bit easier to test for and eventually understand, right?

Next, let’s focus on a slightly more complex type of inheritance that you may not have heard of: oligogenic inheritance. The term oligogenic refers to traits that fall somewhere in the middle of two extremes - not caused by a single gene mutation, but not caused by a multitude of factors, either. Usually there’s a primary gene involved, but it is influenced by other genes (called modifier genes). Think of it like a group project - these traits are formed by a few genes or variants working together (or sometimes against each other) to create an outcome. An example of an oligogenic disorder is Spinal Muscular Atrophy (SMA). In SMA, the spinal motor neurons do not work effectively, leading to varying degrees of muscle movement impairment. The most severe cases result in the inability to move the arms, legs, and neck, as well as difficulty with swallowing and even breathing. Milder forms involve muscle weakness and fatigue. All individuals with SMA have a pathogenic variant (“mutation”) in a gene called SMN1. However, a modifier gene called SMN2 has been identified, and the number of copies of the SMN2 gene present in individuals with an SMN1 gene variant can help predict the severity of SMA the individual may experience.

Finally, we can discuss a type of inheritance that is often overlooked but just as important: polygenic inheritance. As opposed to the other types of inheritance, the term polygenic refers to any trait that involves or requires complex interactions between multiple genes, variants, and additional non-genetic factors to be expressed. Rather than relying on one change in a single gene to create a consistent trait, we can think of polygenic inheritance as more of a mosaic where numerous fragments of information contribute to the overall big picture. When referring to medical conditions, those caused by polygenic traits (such as obesity or kidney disease) tend to be more common as opposed to those monogenic in nature. This is because many factors can contribute to the development of polygenic disease, so there is simply more opportunity for them to develop over time. 

Unfortunately, though polygenic diseases tend to be more common and therefore pretty well understood as far as treatment and diagnosis goes,  it’s a bit more difficult to assess the exact reason for their development. This is due to their multifactorial nature as described above. Rather than looking for a single genetic source to explain the development of a given disease, polygenic risk assessments look for multiple small genetic changes with mild to moderate effect on a given disease and then add each individual risk up to create a cumulative score. This score can then be utilized by healthcare teams to guide discussions about environmental risk mitigation, or be used alongside a patient’s personal and family medical history to develop a more personalized healthcare regimen.

In conclusion, monogenic and oligogenic traits are those caused by genetic changes which follow more straightforward inheritance patterns and cause significant but mostly predictable outcomes. This makes testing for these traits fairly common despite the fact that the variants or mutations associated with them are often very rare. Polygenic traits, on the other hand, are affected by multiple genes, variants, and even environmental factors. This means that though these traits are incredibly common, they can be a bit more difficult to screen for. These three different types of inheritance work together within our DNA to encourage diversity across the human population and help determine who we are. 

We hope you've enjoyed this peek behind the curtain of genetic inheritance. Our next post will examine polygenic testing in additional detail, so stay tuned as we shed light on GenomicMD's clinical specialty: the science and utility of polygenic risk scores.

Blog Glossary:

Monogenic Inheritance - When a genetic trait is controlled by variations within a single gene. From the prefix: mono - meaning one. (Also known as: Single Gene Inheritance; Mendelian Inheritance)

Single Gene Inheritance -  When a genetic trait is controlled by variations within a single gene. (Also known as: Monogenic Inheritance; Mendelian Inheritance)

Mendelian Inheritance -  When a genetic trait is controlled by variations within a single gene. (Also known as: Single Gene Inheritance; Monogenic Inheritance)

Oligogenic Inheritance - When a genetic trait is influenced by a few genes working together (or against each other) to create a specific outcome. From the prefix: oligo - meaning few.

Modifier Gene - A gene that influences the expression of other genes.

Polygenic Inheritance - When a genetic trait involves or requires complex interactions between multiple genes, variants, and additional non-genetic factors to be expressed. From the prefix: poly -  meaning many.

Multifactorial - When a specific trait or quality is dependent on multiple factors or causes to be produced. In medicine, this term usually refers to a health condition that develops due to a significant number of both genetic and environmental causes.