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Early Onset, Treatment Resistant Schizophrenia Linked to Rare Gene Mutation

May 03, 2021

(Part 2 of 2)

In this video, lead author Todd, Lencz, PhD, discusses how his study that identified a rare gene mutation that could result in schizophrenia can apply to future treatment and studies and one day help to develop a prognostic biomarker. In this study, published online in Neuron, researchers identified a single letter change in the DNA code called PCDHA3 that may indicate early onset, treatment resistant schizophrenia.

In part 1 of this video, Dr. Lencz discusses what lead to this study, its methods, and its key findings.

Q: Were any outcomes from the study different than you expected?

A:  We were very excited with the findings that we had, but I do have to admit that we were surprised that we did not find any mutations that were even more common. The Ashkenazi Jewish population has been utilized in many types of genetic studies, and many of you may be familiar with BRCA1, the BRCA1 gene, for breast cancer.

There are also genetic variants that are observed in Parkinson's disease in the Ashkenazi Jewish population that can range up to 5%, 10%, or 15% frequency in patients with Parkinson's disease, Jewish patients with Parkinson's disease, or Jewish patients with breast cancer.

We were expecting to find individual variants that might be found in many of our Ashkenazi Jewish patients with schizophrenia, and the one that we found most commonly was still only observed in 0.3% of our patients with schizophrenia from the Ashkenazi Jewish population.

This was an order of magnitude or even two orders of magnitude lower than what we have observed with diseases like Parkinson's and breast cancer. The reason is that schizophrenia is such a devastating disease.

I probably don't have to explain to this audience, it's relatively early in onset compared to breast cancer and Parkinson's disease. It tends to have an onset, of course, as you know, in late adolescence and early adulthood and tends to interfere with the ability to form relationships and therefore to start families and have children.

There's a strong effect of negative selection on any genes that are associated with schizophrenia, and this causes their frequency in the population to get very low. Even this most frequent gene that we identified, in protocadherin alpha 3, was only observed, as I said, in 0.3% of our Ashkenazi patients with schizophrenia.

We were able to do in our study some modeling of how this would work, and what we showed was that, in our previous work in the Ashkenazi Jewish population, we've demonstrated a very fascinating phenomenon about the Ashkenazi Jewish population: which is that the roughly 10 million or so Ashkenazi Jews alive today worldwide are descended from just a few hundred individuals that lived about 750 years ago.

That's why our genetics are so, relatively speaking, homogeneous. In fact, all Ashkenazi Jews are practically 4th or 5th cousins in terms of genetic similarity, if not in terms of actual family tree.

This was fascinating that even in the context of this relative genetic homogeneity that the effects of negative selection were still strong enough to decrease the frequency of these mutations, but not quite strong enough to eliminate them fully from the Ashkenazi population.

What we were able to show statistically is that with even larger sample sizes, if we have a few thousand patients with schizophrenia instead of 700, we would be able to identify many more genes for schizophrenia.

This is really important because, so far today, even the largest international consortia, with over 25,000 patients with schizophrenia and 100,000 controls from all different populations, has only been able to identify 10 genes in which rare mutations are involved in leading to schizophrenia.

If we can do a similar work at a much smaller scale in the Ashkenazi population, that's one of the big next steps we'd like to take in our research.

Q: Please describe any practical implications for clinicians in the field treating patients with schizophrenia.

A:  In terms of practical or applied clinical implications of our study, in the short run, it's important to emphasize that it takes a very long time to translate genetic findings into potential future treatments.

Our discoveries with respect to the cadherin family of genes is not something that is going to lead to a treatment in the next year or two, or even in five. However, it does lead to very important new lines of research.

That said, another finding of our study that I haven't mentioned yet is that the patients that were carrying this particular mutation tended to have a very early onset and tended to be treatment resistant.

What we want to do to expand this study is try to utilize genetics, and this is something my lab has been doing in several other studies that we've published recently, is utilize genetic information to be able to stratify patients in terms of potential treatment resistance versus treatment responsiveness.

We believe within just a few years, we might be able to develop a prognostic biomarker. That's certainly my goal is to be able to develop prognostic biomarkers to help understand who is likely to respond best to our standard treatments and who might need to go on to, for example, on to clozapine or other treatment modalities.

Q:  Are you conducting any more research in this area? And are there any further studies that you feel are needed?

A:  I wouldn't be a researcher worth myself if I didn't say further studies are needed, and indeed, we are conducting additional studies to get larger sample sizes and identify more genes.

We want to identify enough genes not to necessarily map out every possible gene that we think that, probably hundreds, if not even maybe a few thousand genes, might be implicated in schizophrenia, but to understand the biology a lot better.

As this audience probably knows, our treatments are mostly based on a single mechanism of dopamine D2s receptor blockade that was serendipitously identified in the 1950s, but we want to identify new targets, and genetics is one important way to help unravel the biology.

That's one area that our lab is pursuing, but as I mentioned a moment ago, our lab is also very much involved in trying to synthesize all of this genetic information into a clinically applicable score.

You may have heard the term polygenic risk score, and that's something we work very much on:  to identify a potential prognostic biomarker that could be applied to a patient walking in the clinic you have no history with, you don't know what their background is, or maybe they have no treatment history at all.

Maybe it's a first episode patient and you'd like to have a sense of whether this patient is likely to be responsive to standard D2 treatments, or whether other treatments, including, potentially, clozapine, including perhaps some new medications coming out soon that might have other mechanisms.

Perhaps future mechanisms as well, and neuromodulatory treatments that are being developed, may be more appropriate.


Lencz T, Yu J, Khan RR, et al. Novel ultra-rare exonic variants identified in a founder population implicate cadherins in schizophrenia. Neuron. 2021 Mar 16.[Epub ahead of print].

Dr. Lencz leads the Laboratory of Neurogenomic Biomarkers within the Institute of Behavioral Science at The Feinstein Institutes for Medical Research, Manhasset, New York. He is founder and co-leader of The Ashkenazi Genome Consortium, New York, an international collaboration of leading researchers studying the genetics of complex disease by examining DNA samples drawn from members of this genetically unique “founder” population. Dr. Lencz also leads the international cognitive genomics consortium (COGENT) and is a member of the Psychiatric Genomics Consortium and the Enhancing Neuroimaging Genetics through Meta-analysis (ENIGMA) consortium.

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.

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