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Piecing Together the Genetic Puzzle of Schizophrenia

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One of my more memorable patients was an earnest, caring woman with schizophrenia. Despite some significant side effects from her medications, she had been managing the disorder well for decades. But what stood out most to me was how much she cherished her relationship with her family. Every September, she would show me pictures of her summertime family reunions at a beautiful house on a lake, where she always celebrated her birthday with a big cake — candles and all. Once in a while, she would ask me if we knew anything more about why she had schizophrenia. “It’s the genes, right?” she’d ask, and I could feel the concern behind the question. She was clearly worried that someone else in her family, perhaps one of the freckled young cousins pictured gathering around her cake, might be destined to receive the diagnosis in the not-too-distant future.

Genetics does play a substantial role in the origins of schizophrenia, a role that is both pretty straightforward and incredibly complicated. The straightforward part: genetic differences account for a significant portion of our risk of having a mental illness. The complicated part: determining how these genetic differences contribute to risk is anything but straightforward.

One way to think about it is to consider two very different kinds of genetic traits: (red) hair color and height. Both run in families, but in very different ways. These differences can help us think about the kinds of genetic differences that underlie schizophrenia.

Most people with red hair have it because of a known alteration, or mutation, in the gene for a protein called the melanocortin-1 receptor (MC1R). If you have one or two copies of the unaltered MC1R gene, you will have brown or black hair. But if you have two copies of the altered gene, you’ll have red hair. There are some exceptions to this rule, but, for the vast majority of people, this one gene determines whether they have red hair or not.

The story is very different for height. According to the National Human Genome Research Institute, there are more than 700 genes that can contribute to determining how tall a person will be. It’s the combined action of some of these individual genetic differences, interacting with environmental factors such as diet and exercise, that influence how tall someone is likely to be when fully grown.

It has become clear that the genetics of schizophrenia is less like that of red hair and more like that of height. Over the past six years, NIMH-funded investigators and collaborators around the globe have amassed an impressively large genetics dataset, thanks to the generous participation of more than 60,000 individuals with schizophrenia and almost 100,000 individuals without the disorder. Comparing data from individuals in these two groups, the scientists have identified over 250 places in the genome that contribute to overall risk for schizophrenia. As with height, each one of these genetic risk factors plays a small role in influencing individual risk. Collectively, however, they play a significant role.

These findings are really good news, as each of these 250 risk factors represents an important clue into the biology of schizophrenia. However, the sheer number of risk factors, plus the fact that we still don’t have a clear understanding of how these risk factors interact at the individual level, poses a challenge for those of us who would like to translate these genetic findings into better treatments. How can we study the relevant effects of these genes when we don’t know which combinations are important? Although we have some ideas about how to proceed — for example, we can look for common biological mechanisms shared by multiple genes — it will take a while for us to sort out the best way to learn about schizophrenia from these “small-effect-size” variations.

But is schizophrenia all “small-effect-size” variations? In the past few months, researchers have started to find some rare, larger effect-size differences in single genes using a method called whole-exome sequencing.

Whole-exome sequencing involves reading the DNA sequences of all “protein-coding” genes — that is, all of the genetic information that gets transcribed into messenger RNA and used to make proteins. The exome is a prime target for investigation because we have a good understanding of how the genetic code is translated into proteins and, most importantly, how changes in protein structure can lead to dysfunction. This allows scientists to home in on the genetic differences that are likely to impact the function of proteins and cause disease.

With support from NIMH and other research funding organizations, psychiatric geneticists have been able to sequence the exomes of thousands of people with schizophrenia, and the effort is starting to pay off. A collaborative effort led by Ben Neale, Ph.D., a genetics researcher at the Broad Institute of MIT and Harvard and Massachusetts General Hospital, examined data from more than 2,700 people with schizophrenia and found the strongest evidence to date that rare genetic mutations increase the likelihood of developing schizophrenia. The findings, recently published in Nature Neuroscience, add to unpublished evidence presented at the most recent meeting of the World Congress of Psychiatric Genetics. Presenting on behalf of the SCHEMA (Schizophrenia Exome Meta-Analysis) consortium, Broad Institute researcher Tarjinder Singh, Ph.D., reported findings from a larger exome sequencing study that found several rare genetic variants with large-effect-size changes.

None of these gene variants will lead to schizophrenia in the way that the MC1R variation leads to red hair — an individual’s risk of having schizophrenia is influenced by the combination of many genetic differences with small and large effects, all working in concert. Nonetheless, these whole-exome sequencing findings are game-changing. Why? One reason is that it is much more straightforward to study the biological mechanisms underlying large-effect-size genetic differences in protein-coding genes — researchers can learn about the effects by introducing single gene mutations in human cell lines or model organisms and then looking for changes in molecular and biological processes.

In addition, the biological pathways affected by large-effect-size variations can suggest novel therapeutic targets. One quick example — two of the genes identified in the research presented at the World Congress of Psychiatric Genetics are known to code for receptors for the neurotransmitter glutamate. Researchers had previously hypothesized that drugs affecting the glutamate system may be useful in the treatment of schizophrenia; these new findings give greater credence and specificity to efforts to develop glutamatergic agents as novel therapeutics.

I am thinking now of my patient and her family spending time by the lake in the summer sun. Imagine if we could use these new findings to develop a better treatment for her or a diagnostic test for her cousins. Earlier diagnosis, targeted interventions, a better chance at recovery. These are the goals that inspire us to keep our focus on harnessing these genetic discoveries to help our patients and their families.

Reference

Howrigan, D. P., Rose, S. A., Samocha, K. E., Fromer, M., Cerrato, F., Chen, W. J., Churchhouse, C., Chambert, K., Chandler, S. D., Daly, M. J., Dumont, A., Genovese, G., Hwu, H-G., Laird, N., Kosmicki, J. A., Moran, J. L. , Roe, C., Singh, T., Wang, S-H.,…Neale, B. M. (2020). Exome sequencing in schizophrenia-affected parent–offspring trios reveals risk conferred by protein-coding de novo mutations. Nature Neuroscience, 23, 185–193. doi:10.1038/s41593-019-0564-3