The last few posts (here and here) have been about people who have carrier mutations. These people have one recessive gene mutation that they could pass on to their child. If the child inherits two recessive genes (one from each parent), they will get the disease. That’s how it works with recessive diseases that are caused by one gene. About 4,000 diseases are caused by mutations in one gene (either in dominant or recessive genes). But that leaves all of the other diseases…
Since we’re still talking about genetics, let’s stick to diseases that are caused at least in
part by gene mutations as compared to diseases caused by infection, for example. There are many diseases that are caused by mutations in multiple genes (the technical word for this is polygenic). In these cases, no one gene can be identified as the single cause of the disease. The genes that are involved in causing the disease can be on many different chromosomes in many different locations on these chromosomes and only if mutated in combination will someone get the disease. And these mutations may only cause the disease if exposed to a certain environmental factor (like cigarette smoke).
If this sounds confusing and complicated to you – it is. Scientists find it confusing and complicated too. It’s much more difficult to pinpoint the exact genes that cause a disease if there is more than one mutation in more than one gene. It’s like a puzzle, but you don’t know the number of pieces in advance or what the puzzle looks like. So if you fit two pieces together (or identify two genes that are mutated), you don’t know if you have completed the puzzle and figured out what is causing a disease or if you need to look deeper.
Scientifically, this is a complicated question, but for the patient who doesn’t care how many genes cause the disease, what does it mean to them? What does this mean for risk? If a gene is found to be associated with a polygenic disease, mutations in this gene may increase or decrease your risk of that disease. But unlike genes cause by dominant or recessive genes, no one can say for sure 100% either way if you have a particular gene mutation that you will or won’t get a disease.
A great example of this is Alzheimer’s disease. Only in early onset Alzheimer’s (0.1% of all cases), one dominant genetic mutation the cause of the disease. However, in 99.9% of Alzheimer’s Disease cases, more than one gene is involved (at least three genes, but probably more). One gene that is well studied in association with Alzheimer’s Disease risk is the gene apolipoprotein E (ApoE, for short). There are three different versions of the ApoE gene called ApoE2, ApoE3, and ApoE4 – each representing a different mutation in the ApoE gene. The E2 version (found with 8.4% frequency in the population) is protective against Alzheimer’s Disease. The E3 version (found with 77.9% frequency in the population) is essentially neutral (neither causing or protecting from disease). The E4 version (found with 13.7% frequency in the general population) is the one that causes the problems and and increase the risk from 20% in a person who has zero copies of E4 to 91% risk in a person with two ApoE4 copies. The more copied of E4 the more likely a person is to get Alzheimer’s disease at a younger age as well. And if you’re wondering, this is ABSOLUTE risk, not relative.
Alzheimer’s disease is a particularly tricky example to use because there are few, if any, preventative treatments for the disease. So even if you know that you have two copies of ApoE4, there isn’t much that you can do. However, there are other diseases, where certain genes increase risk for a disease (like I described for the BRCA mutations and breast cancer risk). In this case there are potential preventative treatments, though even after those treatments, the decrease in risk is significant but cannot be eliminated. Overall, it’s important to understand the complexity of disease and how many factors (including unknown factors) can contribute to disease risk and onset. For scientists, knowing the risk factors can help to detect disease early or develop targeted therapies to treat the disease. For doctors, it helps to predict disease risk and tailor treatment. And for the patient, it helps to know that diseases are complicated and risk isn’t 0% or 100%.