COMMENTARY

Genetics and Psychiatry: Let's Proceed With Caution

Jeffrey A. Lieberman, MD

Disclosures

April 29, 2016

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Hello. This is Dr Jeffrey Lieberman of Columbia University, speaking to you today for Medscape. The topic that I want to speak to you about is genetics, which, similar to the Internet or the cell phone, has become a phenomenon that has increasingly and pervasively affected our lives, our thinking, and the environment in the area of healthcare and science.

There are three publications that highlight this fact. Everyone is familiar with the terms "personalized medicine" or "precision medicine." Identification of an individual's genotype will enable better prediction of what illnesses the patient is vulnerable to and lead to specific treatments that are targeted for the gene products. This promises great validity as well as potential, but the time course and the exact way in which it will materialize remain to be seen. Just like the prospect of how the Internet or the cell phone would affect our lives, which nobody could have anticipated at the advent of these systems, genetics is doing the same thing.

As doctors, we read about the progress in research in scientific and medical journals when the evidence reaches a threshold, when it's ready for clinical use. The question is, how is this going to be used and how readily is this going to become a standard part of care?

As with everything else, when it comes to the brain, it's more complicated. When it comes to the part of the brain that is involved with mediating mental function and behavior, it's the most complicated of all. Welcome to psychiatry. However, perhaps sooner than we might have expected and sooner than most technological developments in modern medicine become relevant to psychiatry, genetics appears to be approaching its clinical impact.

This was highlighted in an article[1] that came out in the February issue of Nature. It was published by a group at the Broad Institute in Boston that was headed by Steven McCarroll and Beth Stevens. They described a large, genome-wide association (GWA) study of a huge number of subjects in whom they found a strong association between schizophrenia and a gene on the HLA region of chromosome 6 that codes for complement 4 (C4) protein.

This was a stunning report for a couple of reasons. One was the fact that it was a huge GWA study that reported a robust effect as opposed to a small effect in terms of an association with the specific genetic locus. Also, the particular gene codes for a protein that was associated with theories around schizophrenia for a long time, but for which there had been limited or no genetic evidence. We have long believed that there was evidence supporting the idea that there was some immunologic function associated with the development of schizophrenia, or at least some forms of schizophrenia. However, there was no real evidence for this link other than some genetic association studies with genes in this hypervariable region of chromosome 6.

The other reason is that, in the 1980s, a paper[2] was published by a psychiatrist at University of California-Davis proposing a theory for the pathogenesis of schizophrenia involving excessive synaptic elimination. Schizophrenia tends to have a window of onset in adolescence or early adulthood, a period of time after childhood when brain growth is burgeoning with the production of new cells and new synaptic connections. There is a pruning back that occurs with the perpetuation and hardwiring of connections that have been reinforced by experience-dependent learning. The hypothesis was that, in schizophrenia, something goes awry and the elimination of synapses is excessive and overdone, resulting in a sculpting of circuits that gives rise to this mental vulnerability.

The C4 gene that was reported in the study showed a gain of function in this gene. There were too many copies of it being represented in individuals who had schizophrenia. It linked up directly with the hypothesis and was hailed as a stunning achievement because it gave genetic credibility and underpinning to a very influential pathophysiologic theory. It also pointed the way to treatment development for agents that might influence the process of synaptic elimination.

Even though this was a stunning finding, no one could argue with the fact that a lot still needed to be learned before it was ready for clinical application. Nevertheless, the media, as it is wont to do, hailed this and said that it will soon be used for diagnosis, for treatment selection, and so forth. God willing that that will be the case, but it won't be immediately. So, in something that I've been more inclined to do in recent years, it seemed useful to comment on this phenomenon lest the public or the media get carried away and ask for these things from their doctors or resort to recreational genetics companies like 23andMe.

I and a colleague, Ogi Ogas, wrote an article[3] that was published in the Wall Street Journal on March 3, which essentially tried to not throw cold water on this finding but to add a cautionary note. Even though this is a very important scientific achievement, it doesn't mean that we are going to be applying it soon, much less realizing what I think many people see as the ultimate potential of precision medicine, which is designing human beings using techniques like CRISPR to edit genes in the embryo—deleting genes that may be bad in terms of causing disease, and editing genes that might be desirable in terms of personal characteristics and the like.

The article was trying to put this in perspective in a historical context, and the historical context, like so many things having to do with psychiatry and mental illness, was a checkered one. The origin of psychiatric genetics actually began in the late 19th century with Sir Francis Galton and the theory of eugenics. This was carried over to the United States, and by 1960, some 60,000 people with mental illness in the United States had been forcibly sterilized. This was due to the idea that genes caused mental illness and ran in families, and that if we eliminated it, we could perhaps alleviate mental disabilities from the population. Of course, this was disastrous, unethical, and unscientific. Nevertheless, it provides a powerful cautionary note.

Just to illustrate how genetics has exerted a pervasive influence in the public sector, Siddhartha Mukherjee, a colleague of mine at Columbia who is an oncologist, announced that his second book will be published in June. It is called The Gene: An Intimate History. Sid had previously published The Emperor of All Maladies, which is a biography of cancer. It's a fabulous book that won a Pulitzer Prize, and one of the reasons for that is his unique writing style in which he traces history and weaves in the science. He also adds his own personal experiences as a clinician training in oncology. However, in The Gene, which he describes as a history of genetics, his personal experience is his own family's history of mental illness.

His family has a pedigree that is chock full of individuals affected by mental disorders such as schizophrenia, bipolar disorder, suicide, and depression. Sid courageously describes these in very compelling and poignant detail and, in doing so, illustrates the way that genes exert their influence in families that is not in known patterns of inheritance or mechanisms of transmitting this vulnerability.

All of these types of publications—an article in the scientific literature, a news op-ed piece, and a book that tells an important scientific and personal story—illustrate how important genetics is becoming in our society. I emphasize in conclusion that, although the media tries to convey this to the public when there are newsworthy findings, it's essential for physicians, scientists, and clinicians to keep our heads about us, utilize the information in a prudent and scientifically justified manner, and help our patients and the population to understand genetics and the power that it holds for humanity and healthcare. We must prevent expectations from getting inflated, as well as any individuals within healthcare or related enterprises from using this for inappropriate purposes.

I recommend these three publications to you if you're interested. Thank you for watching. This is Dr Jeffrey Lieberman for Medscape, at Columbia University.

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