The genetic basis of disease

Many diseases are influenced by genetic variations in an individual’s genome. We refer to these diseases as “genetic diseases,” because the risk of developing such a disease can be impacted by your genetic makeup. Now, in order to understand the genetic basis underlying these diseases, we need to understand how genetic variations contribute to disease.

Consider all the diseases you’ve ever heard of to be on a spectrum. On one end of the spectrum, we have monogenic, or single-gene disorders. This means having a mutation in one single gene can cause a genetic disease, such as Cystic fibrosis or Huntington’s disease. On the other end, we have polygenic diseases, which are diseases influenced by the combined effects of many genes. This end of the spectrum includes more common diseases in the population, such as coronary heart disease and Type 2 diabetes. Since many genes are involved, the genetic basis of polygenic diseases are more complex than monogenic diseases.

So, how do you determine your child’s risk of developing a genetic disease? To answer this question, we need to dive deeper into some of the differences between monogenic and polygenic diseases, how we test for them, and why this information is important when we consider family planning.

Monogenic diseases are rare and caused by a single gene

Monogenic diseases are caused by mutations in a single gene. These diseases tend to be rare, more severe, and affect far fewer people than polygenic diseases. Some well known monogenic diseases include:

• Sickle cell anemia 
• Cystic fibrosis
• Tay-Sachs disease
• Hemophilia 
• Huntington’s disease

Over the years, geneticists have found over 4000 genetic diseases caused by mutations in a single gene. Although each monogenic disease is rare, collectively they affect about 30 million people in the United States, and roughly 300 million people worldwide. So when we add them all up, they aren’t so rare after all.

Since many monogenic diseases are often inherited from our parents, we also refer to them as “hereditary diseases.” When a child is conceived, they inherit two copies of each gene from their parents, one from their mother and one from their father. Different combinations of these copies can determine whether or not the child can develop the disease. Depending on the disease in question, there are a few ways in which they can be inherited from our parents:

• autosomal dominant inheritance, where only one copy of a faulty gene (this can be from either parent) is necessary to cause the disease. 
• autosomal recessive inheritance, where two copies of a faulty gene (one from each parent) are necessary to cause the disease. 
• X-linked inheritance, where the faulty gene is only present on the X-chromosome, the female chromosome.

Regardless of how the disease was inherited, monogenic diseases are easier to test for than polygenic diseases, because we simply need to look for the presence or absence of a faulty gene.

Polygenic diseases are multifactorial

The vast majority of diseases we are familiar with are actually polygenic diseases. These diseases are influenced by genetic variations in many genes. They are also often influenced by many environmental factors, like nutrition, exercise, and environmental exposures. Since most polygenic diseases are determined by the interactions of several genes and environmental factors, we call them “complex” or “multifactorial” diseases.

Polygenic diseases typically affect millions of people in the population, and are usually diagnosed during your adult years. Type 2 diabetes affects more than 37.3 million Americans (that’s 11.3% of the US population!) and of these roughly 8.5 million are undiagnosed. An additional 96 million Americans over the age of 18 years are considered prediabetic, meaning they have a high risk of developing Type 2 diabetes. Imagine if you knew that your child’s risk was higher for developing Type 2 diabetes. Perhaps you would alter their lifestyle to include more exercise and sports. The reason polygenic diseases affect so many people is because they all involve so many different genes - often in different combinations - that interact with different environmental factors to cause the disease. See why they are so complex?

And although complex diseases tend to cluster in families, their inheritance isn’t as clear cut as monogenic diseases. We are still trying to figure out why some members of a family develop the disease, while others don’t. Unlike monogenic diseases which are much simpler to test for, polygenic diseases require a much more complex assessment (we’ll get into this in the next section).

Some common polygenic diseases include:

• Coronary artery disease
• Type 2 diabetes
• Alzheimer’s disease
• Cancer 
• Schizophrenia

Preconception screening for monogenic and polygenic diseases

For monogenic diseases

For single-gene, monogenic diseases, couples can undergo carrier screening prior to conception. Carrier screens assess prospective parents’ DNA to determine if they are carriers of a gene that causes a rare genetic disorder. When we say carrier, we mean that they “carry” the faulty gene that can be passed down to their children, even if they do not have the disease themselves. The results of these tests tell you whether you are likely to be a carrier of genetic disorder or not. You can then use that information to determine your future child’s risk of developing a rare genetic disorder.

Carrier screening is extremely valuable for assessing monogenic conditions, but it can’t help us predict genetic risk for more common, polygenic diseases which affect millions more people.

For polygenic diseases

Predicting genetic risk for polygenic diseases is far more complex than carrier screening. How do we know which genetic variations are important and which ones aren’t?

With advances in genomics and massive DNA databases, scientists can determine which variations increase or decrease risk of a particular disease. This information is then used to calculate a polygenic risk score, which estimates an individual’s genetic risk of developing a complex disease based on their unique genetic variations.

It’s completely normal for most people to have thousands of genetic variations in their genomes. Some are harmful, some are beneficial, but most really don’t have any significant effect. Each variation alone only has a tiny effect on causing the disease, but many of these variations together can greatly impact one’s susceptibility. This is the crux of polygenic risk scores: using the cumulative effects of all the genetic variations in a person’s genome to determine whether their probability of developing a disease is lower or higher.

This new tool allows us to better assess how our genetic makeup impacts our susceptibility to complex, polygenic diseases, and how that might impact our future children’s health.

Ways you can be proactive with this information

Many couples now opt for genetic screening before or during pregnancy. At Orchid, our Couple Report gives you unparalleled insight into how your genetics might impact your future child’s risk to develop common, polygenic diseases.

It’s important to understand that a polygenic risk score is a probability, not fate. The question then becomes: what can we do with this information? We believe that knowledge is power at Orchid. Couples can use our reports to make informed choices about family planning, embryo screening, and lifestyle modifications to maximize their chances of bringing and raising a healthy child in this world. While you might not be able to change your genetic risk, you can certainly explore early interventions and lifestyle adjustments to offset it, and apply these same preventative measures for your children.

Orchid offers advanced genetic testing for couples planning on building their family. We use advanced tools and smart, caring humans to help you give your future children the best shot of a healthy life. Conceive with greater confidence and peace of mind