One possible reason why schizophrenia is so common

And how mom and dad affect your chances of getting it

by Dr. Barry Starr

Schizophrenia affects over 2 million people in the U.S. That is close to 1% of the U.S. population.

This is surprisingly common for such a devastating illness. And its frequency is even more puzzling because genes play such a large role in schizophrenia (click here to learn more).

Usually genes that would affect someone as severely as schizophrenia would become less common over time. But this isn't the case for schizophrenia.

Sometimes harmful genes hang around if there is some sort of benefit to having the altered gene in the population. The classic example of this is sickle cell anemia.

People with only one version of the HBB gene that leads to sickle cell anemia are more resistant to malaria. This is definitely a survival advantage in certain parts of the world. So even though having two copies causes severe problems, the gene version is maintained because of the advantage of having a single copy.

No obvious benefit for the schizophrenia version of multiple genes has yet been identified though. So why is schizophrenia so common? A couple of recent studies are starting to shed light on this difficult question.

One study suggests that part of the answer has to do with the genes of both mother and child and how they interact. Sometimes if a gene is too similar between the two, the child is at increased risk for schizophrenia. And sometimes if the genes are too different, the child is at increased risk.

In other words, having a gene is sometimes harmless and sometimes having it increases your risk for schizophrenia. It depends on mom's genes.

But don't just blame mom. Dad can affect his child's chances of getting schizophrenia as well. Apparently, as a dad gets older, his sperm develops new mutations that can lead to an increased risk for schizophrenia.

These new DNA changes increase the frequency of schizophrenia genes in the population. Even if some gene versions that lead to schizophrenia were becoming less common, these new mutations might offset them. The end result is a constant supply of schizophrenia causing genes.

Mom and schizophrenia

For many diseases
DNA is not enough

Some genes only increase someone's risks for getting a disease. To actually get the disease, something in the environment has to trigger it. So the gene isn't enough by itself.

There are a lot of diseases like this out there. Diabetes, Parkinson's disease, Alzheimer's, and schizophrenia come to mind as examples.

But in almost all of these cases, the specific environmental trigger isn't known. Scientists come up with all sorts of explanations including chemicals or infections but they don't know for sure. Except now maybe for some cases of schizophrenia.

Some recent studies suggest that how a child's gene responds to the environment of mom's womb can affect a child's chances for developing schizophrenia. And this environment is dependent on mom's genes.

Part of this environment is set up by mom's immune system. Problems can happen when mom's immune system responds to her child's genes in certain ways. Or fails to respond.

As you know, we have immune systems to repel any foreign invaders like bacteria or viruses. The way the immune system does this is by recognizing foreign proteins.

For example, imagine someone has a viral infection. The virus has genes that are not found in the person. These genes are instructions for proteins.

Some of these proteins are on the outside of the virus. The immune system looks over the virus and sees a protein it hasn't seen before. The immune system then attacks and wipes out the virus.

Now, instead of a virus imagine that the "invader" is a fetus. The fetus makes some proteins that mom does not. Why doesn't mom's immune system attack?

Well, sometimes it does. The classic example is something called hemolytic disease of the newborn. In this case, mom's immune system attacks her fetus' red blood cells because they have a foreign protein, the Rh factor.

With blood type, we are all Rh+ or Rh-. Rh- actually means that the person doesn't make any Rh protein.

Imagine a mom who is Rh- and a baby who is Rh+. What will happen?

Well, unless there is a mixing of the blood, not much because the fetus is pretty well contained. But blood mixing does happen, particularly at delivery.

What happens next is that mom's immune system makes antibodies to the Rh protein. And the next child is at risk if they are Rh+.

They are at risk for hemolytic disease because mom's immune system attacks the baby's red blood cells. Apparently this attack leads to around a 2-3 fold increased risk for schizophrenia as well.

No one is sure why this is although it probably has to do with a lack of oxygen to the baby and possibly the build up of bilirubin in the fetus' blood. These probably affect the brain development of the fetus in such a way that the risk of schizophrenia is increased.

The environment of the womb
can affect a child's chances
for developing schizophrenia

Now, if the mother and fetus were both Rh+, this gene would not be a risk factor for schizophrenia. It is only when mom is Rh- and the fetus is Rh+ that the Rh gene becomes a risk factor.

Now this kind of makes sense to me. A mother's immune system that attacks a child's blood is going to cause all sorts of problems. But weirdly enough, problems can arise if the mother and child's genes are too similar too.

A recent study by the same group showed that if mom and baby had a very similar HLA-B gene, then the chances for schizophrenia go up 1.7 fold. What is going on here?

Clearly having the same gene shouldn't affect the baby in the same way that having different genes would. What seems to be going on is that a successful pregnancy needs mom to make some antibodies to a fetus (or at least to certain proteins of the fetus).

Why this should be this way is unclear. For some reason, a successful pregnancy needs a certain level of reaction to a fetus. Or at least to HLA-B protein.

What this does show is how the environment and genes can interact to cause a disease. Imagine that Johnny has a certain HLA-B gene. If his mom has the same one, then he is at increased risk for schizophrenia. If mom has a different one, then he isn't at an increased risk.

This particular version of HLA-B is a risk factor for schizophrenia only in certain situations. If mom has a different version, then having this version of the HLA-B is fine.

Which might help to explain why schizophrenia remains so common. These genes are only harmful in some situations and not others so there may not be a strong selection against having them.

More Information

Dad and Schizophrenia

Dad's age can affect your
chances of getting
schizophrenia

Society often shakes their head at older women becoming moms. With the increased risk for birth defects, miscarriages, etc., why would they wait so long?

It is different for men though. An 80-year-old man who has a child is championed by society. This is partly because people believe there is little risk in older men becoming fathers. And those people couldn't be more wrong.

The older a dad, the more likely it is that their children will suffer from a number of problems. These problems include a rare disease called Apert syndrome, autism, Down syndrome, miscarriage and schizophrenia, just to name a few.

Why all the problems? They have to do with how a man makes sperm.

Men are constantly making sperm from puberty until death. To make a sperm, cells need to divide and DNA needs to be copied. And each time DNA is copied, there is a chance for an error.

So, as he churns out 1500 sperm/second, an occasional mistake happens. If that mistake is in a gene that can cause schizophrenia, then the child will be at an increased risk.

As a man ages, there is a build up of these damaged sperm so the odds of a damaged one fertilizing an egg gets higher. Men in their 50's are three times as likely to have a child with schizophrenia as compared to 25 year old dads.

These spontaneous mutations increase the number of schizophrenia gene versions in the population. So even if some gene versions that lead to schizophrenia were becoming less common, these new mutations might offset them.

The end result is a constant supply of schizophrenia causing genes. This plus the environment of mom's womb might help explain why schizophrenia remains so common.

More Information

Paternal age and schizophrenia

Content provided by the Department of Genetics, Stanford University.