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Rare Gene Mutation Could Result In Schizophrenia
(Part 1 of 2)
Researchers identified a gene mutation that could result in schizophrenia, leading to possible novel treatment strategies, according to a study published online in Neuron. Researchers identified a single letter change in the DNA code called PCDHA3 that is associated with schizophrenia.
In this video, lead author Todd Lencz, PhD, discusses the impetus for the study, the study methods, and most significant findings. In the upcoming part 2, he discusses surprising findings and practical applications of this research to clinical practice.
I’m Dr. Todd Lencz, I’m a professor of psychiatry and molecular medicine at the Zucker School of Medicine at Hofstra Northwell, Uniondale, New York, and I am the director of the Laboratory of Neurogenomic Biomarkers at the Zucker Hillside Hospital division of Northwell Health, Glen Oaks, New York.
Q: What was the impetus for your study on rare exonic variants associated with schizophrenia?
A: We’ve known, as a field, for many decades that schizophrenia tends to run in families and has a strong genetic component. It is not a simple Mendelian disorder like Huntington’s disease where there’s a single gene involved.
We know that it’s a complex disorder with a complex pattern of inheritance and that many genes are involved. In the field of psychiatric genetics which is the field that I work in, the challenge has been to identify what genes are involved. We know that the penetrance is low, so identifying those genes is very challenging.
An additional challenge is the fact that there is a tremendous amount of heterogeneity in the disorder, schizophrenia, and there’s a tremendous amount of heterogeneity in the genomes of all people. Finding genes for schizophrenia is a needle in the haystack problem.
What we wanted to do was to examine the genetics of a very specific population, the Ashkenazi Jewish population which is much more homogeneous.
With the hopes that, by examining patients with schizophrenia and non-patient, healthy comparison subjects all drawn from the Ashkenazi Jewish population, that this would help reduce that level of homogeneity and increase our chances of finding that needle in a haystack.
I should emphasize at the outset that there is no association between being Jewish and having schizophrenia. This is not something where Ashkenazi Jews, such as myself, are at heightened risk for schizophrenia due to genetics.
We’re just simply studying the genetics within this population because we hope that it might be slightly simpler, not simple, but a little bit less heterogeneous.
Q: Please briefly describe the study method and most significant findings.
A: In order to accomplish our goal of finding genes associated with schizophrenia, we were particularly interested in identifying what are called rare variants, and in fact, what are called ultra-rare variants.
These are mutations that are found in very, very few, if any individuals, in the healthy population. At first, we took about 786 patients with schizophrenia and 463 healthy comparison subjects. All subjects, as I said, drawn from the Ashkenazi Jewish population, recruited both in Israel and in the United States.
We did something called whole genome sequencing, and we particularly focused on an area of the genome called the exome which is the one to two percent of the genome that is involved in coding for proteins.
What we were looking for were mutations that were not observed in other databases, public databases, of over 100,000 healthy individuals. We screened out any variance, and this is part of the heterogeneity of the human genome, is that each individual, you, me, anyone, has millions, literally millions of variations compared to any other human.
Now, that still means that we have 99.9% of our genomes in common from one person to the next, but it’s that little bit of difference that adds up into being millions of variations since there are billions of letters, A, G, T, and C, in the human genome. There are billions of those letters, so even a few million is a small percentage but it’s a large search space.
We took ultra-rare variants that were only identified in our subjects and not been reported in public databases, and we examined those that were exclusively found in patients with schizophrenia.
We looked specifically for mutations that were observed in genes more than once in patients with schizophrenia and were found more than twice in patients with schizophrenia. We examined those genes in which none of our healthy controls had had a mutation.
We looked to see what those genes had in common and what we could learn about the possible genetics of schizophrenia from examining those genes. We found a number of interesting genes relating to neurodevelopment, to synaptic formation, but in particular, these are some genes that had been found previously in other studies.
What was novel to our study was identifying a series of genes in cadherin proteins, and cadherin proteins are very special types of proteins that are involved in the scaffolding that holds together the synapse.
Digging further into our data, we identified one mutation, in particular, that was observed in more patients than any other, and it was in a gene called protocadherin alpha 3. What that told us, we were then able to take that mutation and insert it into an in vitro culture version of that gene and that protein to see how the protein output of that would be different.
What we discovered is that that protein which was supposed to go to the plasma membrane where it can form that synaptic scaffolding instead remained in the cytoplasm of the cell and did not go to the cell membrane and did not, what we call, dimerize.
Did not adhere to itself to create a particular molecular structure, but instead remains scattered throughout the cell. This is a novel mechanism that we were able to identify as potentially having an important role in the biology of schizophrenia. Now, what’s important to mention here is that this mutation was found in a few of our patients.
This is not something that is going to be found in even 1 percent of all patients with schizophrenia or even one percent of all Ashkenazi Jewish patients with schizophrenia. This is giving us a very important clue as to the type of neuronal abnormality that may underlie schizophrenia.
Our hypothesis is, and this will require further study, of course, is that many of the mutations that the genetic heterogeneity that I’ve described in schizophrenia, which is vast and quite different from one patient to the next, may, in fact, converge upon a few biological pathways of interest. These may have specific clues to novel treatment technologies and novel approaches.
Reference
Dr. Lencz was among the first recipients of the EUREKA (Exceptional, Unconventional Research Enabling Knowledge Acceleration) award from the National Institute of Mental Health (NIMH), Bethesda, Maryland. He has previously received a Career Development Award from NIMH, as well as a Young Investigator Award and an Independent Investigator Award from the Brain and Behavior Research Foundation. Dr. Lencz has also served as Chair of several grant review panels at the National Institutes of Health.
