Sunday, January 25, 2015

Schizophrenia & the Heritability of Mental Illness

In the past decade, genetics have burst our approach to mental illness wide open, and some of these major findings have trickled into main stream media distilled into the doom-and-gloom prophecy that serious mental illness is “genetic” and therefore may not be able to be prevented or treated in many people. The purpose of this week’s article is to clarify some of the “it’s all in your genes” lore. Remember that one of the cornerstone principles of SFW is that most science journalism is NOT written by scientists, and therefore may misinterpret much of what was actually done by the research team.

Don’t get me wrong, genetics are fascinating, and the brilliant minds that have been shaping this field in mental illness are nothing short of remarkable. However, they will also be the first to tell you that genes are not the only answer to how individuals develop mental illness, because even if genes make up most of the story, there is a process by which genes can be “turned on and off” by the environment through a process called methylation. Essentially, most of us are comprised of genes to live in the environment our parents lived in, but also built to only use these genes as necessary given that environments change over time and humans travel through different environments frequently. Using some now famous studies of identical and fraternal twins, we determined that mental illness is “heritable,” or the product of genes. What we are learning more recently, individuals are not inheriting illness from their parents through one gene, but rather several that need to be “turned on” together. 

This week, I will briefly review a recent study published in the American Journal of Psychiatry by Javier Arnedo and his colleagues in the Department of Computer Science and the Department of Psychiatry and Genetics at Washington University. The article was sent to me by one of my favorite people, now a medical student at Tufts University and U.S. Navy Medical Service Corps Officer, Julia Jacobs.

The article is about the genetics of Schizophrenia, which is a serious mental illness that occurs in about 1% of the population. Based on twin studies, Schizophrenia is considered highly heritable or “genetic.” Briefly, individuals with Schizophrenia typically first experience flat affect (limited facial expressions, monotonous tone of voice), and loss of interest or pleasure in activities and social interactions. These are referred to as negative symptoms and can be confused with depression. Individuals with Schizophrenia also experience what we refer to as positive symptoms, including disorganized thoughts and speech, hallucinations, and paranoia. A common misconception about people with Schizophrenia is that they are dangerous, however the incidence of violence among people with this illness is low, and among those who may be dangerous the violence is self-directed as 10% of people with this illness commit suicide. For more on what we currently know about Schizophrenia, check out this page organized by the NIMH ( Schizophrenia has also been made familiar and accessible to mass audiences through such films as Out of Darkness, A Beautiful Mind, and The Soloist. 

What I learned in this article from the outset was that while Schizophrenia is 81% heritable, only 25% of variability is explained by specific genetic variants according to traditional methods used in genetic studies. So where is the rest coming from? And why such a big gap? 

Arnedo and colleagues, in this study, tried better characterize what we call Schizophrenia and the genetic markers that may lead to the illness.

To do this, they used genetic information gathered from the blood of 4,196 cases and 3,827 controls from the Molecular Genetics of Schizophrenia study. Among these participants, they identified patterns of genetic polymorphisms (SNPs) that cluster within individuals (without regard for whether they have Schizophrenia or not). This resulted in 723 clusters. Then, they calculated the “risk” for having Schizophrenia from each of these clusters, and identified 42 genetic polymorphism clusters that were associated with a 70% or greater increase in risk for having Schizophrenia. They then re-tested the association between these genetic polymorphism clusters and risk for Schizophrenia in two other studies of Schizophrenia with more than 1000 more people.

The research team then identified distinct clinical features (phenotypes) of the individuals in the MGS study that account for different presenting symptoms of Schizophrenia (primarily positive symptoms versus primarily negative symptoms), different trajectories of the illness (people who became very ill very quickly, versus those whose onset was more slowly progressing). Once they identified clinical features that were distinct, they calculated the association between each of their genetic polymorphism clusters and these clinical features. They found that some genetic clusters were associated with their clinical features. Again, they re-tested their findings in two additional large samples.

The result of this highly complex and tedious work was 8 genotype-phenotype relationships and concluded that what we call Schizophrenia today may actually be several distinct clinical syndromes with different genotypic networks. By identifying these genetic polymorphism clusters, the research team was able to account for 90% of the clinical cases, which is much improved from the 25% accounted for by past approaches. Unfortunately, this creates a problem for anyone who studies Schizophrenia, given that it is already challenging to study a phenomenon that occurs in 1% of the population, but now those subgroups are likely even smaller. Alas, we would not be scientists if we didn’t want to conquer the seemingly impossible. 

So, if you’re still with me, you may be wondering why I found this to be relevant to SFW readers. when only 1% of the population has this illness. To me, this article speaks volumes about genetics and mental illness outside of Schizophrenia. There seems to be a lore out there in the public forum that if something is “genetic” then there is a single gene for that single ailment. This study is evidence to me that genetics are far too complex to be distilled into such a misconception. There is no “Schizophrenia gene,” instead, there are clusters of genes that when present together predict important features of each disorder. In the case of this article, there may be clusters if genetic predictors of “hallucinations” and a different set of genetic predictors of “disorganized speech.”
I know a few young people who have faced incredible obstacles in their short lives so far. In some cases, there was a parent with a mental illness who started a hurricane of difficulties for these people, one wave of which was the belief that “this will be me one day,” as though it were unavoidable and inevitable. That’s really only helpful if you are going to actively seek prevention, but inevitability tends to lead people to believe that prevention is futile. Research on genetics and mental illness is one of the best examples of how science is grossly misrepresented by journalists and then the public through social media. Ultimately, it’s the responsibility of scientists who often don’t communicate clearly enough.

Furthermore, I would be remiss as a clinical psychologist if I didn’t mention that this article also speaks to common stereotypes about mental illness. Schizophrenia has many faces and usually won’t look like Russell Crowe in A Beautiful Mind. This goes for many different forms of mental illness. Don’t dismiss a person’s suffering because it doesn’t always look the same. The best, and most far-reaching example I can give of this, is the mood difficulties common to depression. Sometimes depression can look like sadness and isolation, other times it can look more like irritability and anger, but both cases indicate equal human suffering. The homeless person outside your neighborhood park may be unusual, but they are still a human being who seeks to be understood.

Arnedo, J., Svrakic, D. M., del Val, C., Romero-Zaliz, R., Hernández-Cuervo, H., Fanous, A. H., ... & Molecular Genetics of Schizophrenia Consortium. (2014). Uncovering the hidden risk architecture of the schizophrenias: Confirmation in three independent genome-wide association studies.


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