Future Tense

The Search for Schizophrenia Genes

Larger and larger samples are showing smaller and smaller effect sizes. What does this mean for drug development, clinical practice, and our view of mental illness?

Researchers’ efforts to uncover schizophrenia genes have not been very illuminating.

Photo illustration by Lisa Larson-Walker. Photo by Victor_Tongdee/Thinkstock.

This article was adapted from an essay in Issues in Science and Technology.

Last week, according to many media accounts, scientists from Harvard Medical School, Boston Children’s Hospital, and the Broad Institute discovered the genetic basis of schizophrenia. The researchers reported in Nature that people with schizophrenia were more likely to have the overactive forms of a gene called complement component 4, or C4, which is involved in pruning synapses during adolescence. However, suggesting a biologic mechanism for a small subset of those diagnosed with schizophrenia is not the same as confirming the genetic theory of schizophrenia. Benedict Carey, science reporter for the New York Times, delved into the details and reported the all-important fact that having the C4 variant would increase a person’s risk by about 25 percent over the 1-percent base rate of schizophrenia—that is, to 1.25 percent.

Genes for schizophrenia and depression have been discovered before, and in those cases, the subsequent enthusiastic headlines were shortly followed by retractions and more sober thinking. There are so many open questions (for instance, why do many people with the problematic variant not develop schizophrenia, and why do many people who don’t have the variant develop schizophrenia?) that the same may occur with the C4 discovery.  

The idea that mental illness is the result of a genetic predisposition is the foundation for modern-day psychiatry and has been the driving force for how research money is allocated, how patients are treated, and how society views people diagnosed with conditions identified in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition. Schizophrenia holds a unique spot in the annals of mental health research because of its perceived anatomical underpinnings and is often cited as evidence in favor of a genetic predisposition to other conditions.

From about 1970 to 1990, a series of family, twin, and adoption studies were used to estimate the heritability of schizophrenia from 42 percent to 87 percent—a figure that some geneticists believe is an estimate of how much genetics might explain rates of schizophrenia not within individuals but within a population. Although the technology at that time was not advanced enough to identify the specific genes involved, it was assumed that technological advances would eventually catch up and pinpoint the genetic culprits. Once the genes were discovered, biological markers would be identified, which, in turn, would lead to the development of precision drugs.

The technology has now caught up, and we are firmly entrenched in the molecular era of behavioral research. Yet, in spite of the fact that molecular geneticists have spent countless hours and millions of dollars, a specific “schizophrenia gene” has never been found. Decades of research have confirmed that the influence of genetics on psychiatric conditions is relatively minor and that those earlier studies misjudged heritability estimates.

Even for many common physical conditions with clear biological pathology, the Human Genome Project has shown that there are hundreds of genetic risk variants, each with a very small effect. As geneticists implicate more and more genes and the importance of each individual gene decreases, it becomes hard to see how this information can be used in a clinical setting. Compared with these physical conditions, the debate about genetic risk factors for psychological conditions such as schizophrenia, depression, and attention deficit hyperactivity disorder, which all lack distinct biological markers, is even more heated.

The current trend in psychiatric genetics is to use enormous samples to find genes of miniscule effects. In May 2014, the Schizophrenia Working Group published “Biological Insights From 108 Schizophrenia-Associated Genetic Loci.” The genome-wide association study, involving rapidly scanning markers across complete sets of DNA for many people, looked at 36,989 patients and 113,075 controls and identified 108 loci with genome-wide associations. The risk scores explain only up to 4 percent of the variance in the diagnosis of schizophrenia. To complicate matters, these same genes have been implicated in other conditions, such as ADHD and autism. In his book Misbehaving Science, Aaron Panofsky, an associate professor in public policy at the University of California, Los Angeles, discusses the strategies that behavioral geneticists use to cope with the failure of molecular genetics. In his words: “One of the most basic strategies for dealing with the disappointment of molecular genetics has been to lower expectations.”

A genome-wide scan that did not show a major role for genes would seem to be a problem for the genetic theory, yet popular outlets like Scientific American enthusiastically celebrated the fact that the researchers found at least something. But even a fairly enthusiastic article in the Lancet Psychiatry admits that genetics cannot be used to make clinical predictions. While the actual results were not that impressive, this did not stop some behavioral geneticists speculating that in the future, researchers may discover more than 8,000 variants for schizophrenia. Yet, as more and more variants are implicated, the results become so watered down that a clinically useful signal appears impossible to distinguish from the noise.

As Kenneth Kendler, a psychiatry professor and geneticist at Virginia Commonwealth University, concluded in a recent paper, “All of us carry schizophrenia risk variants, and the vast majority of us carry quite a lot of them.” It is only by combining all the genetic markers into a single polygenic risk score that researchers can say that an individual has an increased risk of developing schizophrenia. However, even those individuals with a supposedly increased risk were more likely to not develop schizophrenia.

All of this holds enormous implications for psychiatry. The widespread use of psychiatric medications is based on the idea that schizophrenia and other psychological conditions arise, in part, from genetic defects that result in biological alterations such as reduced levels of neurotransmitters, or deficits in neuronal circuits, that need to be fine-tuned with medications. In general, higher genetic contributions to a disease equate to a stronger case for pharmacological treatment, while diseases with a higher environmental component are seen as better candidates for lifestyle changes and therapy. In 1996, in regard to ADHD, Stephen Faraone, a leading psychiatric genetic researcher, stated: “Many parents are reluctant for their children to take psychotropic medication and others find it difficult to maintain prescribed regimes. These problems are mitigated by discussing the genetic etiology of ADHD. …” If parents really believe that their child has a measurable chemical imbalance, then just as they would treat their diabetic child, they would surely treat their child diagnosed with ADHD. Most of the stimulant manufacturers have also promoted this idea in their advertisements.

Even if genetics are implicated in a disease, development of the disease is not inevitable. Given the right environment, the disease will not necessarily develop. Post-traumatic stress disorder is seen in veterans and abused children, for instance. Even if there is a genetic component to PTSD, it is still entirely preventable by removing the environmental stressor—not going to war or not growing up in an abusive household. With no biological markers that can be used to identify mental illness, even the diagnosis of these conditions is subject to society’s vagaries of what is considered abnormal. In America, 9 percent of school-aged children are diagnosed with ADHD, while in France it is less than 0.5 percent. It is unlikely that this is the result of a genetic difference between American and French children.

For most biologists, the nature-vs.-nurture debate is not an either/or debate but is about the relative contributions of each. Taking the 108 loci study at face value, one could conclude that genetics plays a role—but not much of one. A growing number of studies have shown that various environmental insults during childhood, such as sexual, physical, or emotional abuse, peer victimization, and parental loss are risk factors for schizophrenia. A recent study, “Accumulated Environmental Risk Determining Age at Schizophrenia Onset,” found that the environmental factors, but not genetic factors, were major risk factors for schizophrenia onset. Because early cannabis use—an avoidable risk factor—was an environmental predictor, the authors suggest the need for increased public awareness. At least in terms of prevention, it appears that the focus should be on the environment.

There is nothing wrong, per se, with looking for genes of very small effect, but with no single gene emerging as a culprit, the justification for this research is weak. We now know that biomarkers or specific genes for psychological conditions do not exist, that this research will not lead to magic pharmacological bullets, and that many of our assumptions about mental illness were wrong. The message for the psychiatry community is to rethink how it treats patients, how it allocates research money, and its emphasis on the biological treatments of psychological conditions.

But this is wishful thinking. UCLA just announced the investment of $250 million into the “Depression Grand Challenge.” In a statement reminiscent more of a marketing program than an accurate scientific appraisal of the field, Nelson Frelmer, professor of psychiatry and biobehavioral science and director of the Center for Neurobehavioral Genetics at UCLA, claimed that “advances in technology for genetic research have now made it possible for us to discover the causes of depression. We know a genetics-based strategy will be successful, just as it has been with heart disease, diabetes, and cancer.” The press release declared that this investment will make it possible for researchers to first discover the causes of depression through the largest-ever genetic study for a single disorder and to then use these findings to “examine the molecular mechanisms and brain circuitry through which genetic and environmental factors lead to depression.” Is it really possible that all we needed to solve the problem of depression—a condition strongly influenced by environment—was 10 years and $250 million? The reality is that it hasn’t worked for schizophrenia and other psychological conditions, so there is little reason to believe that it will work for clinical depression. 

Future Tense is a collaboration among Arizona State University, New America, and Slate. Future Tense explores the ways emerging technologies affect society, policy, and culture. To read more, follow us on Twitter and sign up for our weekly newsletter.