Schizophrenia Daily News Blog

Research Identifies Method of Quantifying Schizophrenia Risk

It has long been known that people with schizophrenia suffer from certain cognitive and neurological abnormalities and disabilities. These are widely understood to be markers for the disease -- what the research community calls endophenotypes of schizophrenia. But what exactly is the relationship between the markers and the disease? Does the presence of one or more markers predict schizophrenia or indicate risk for developing it?

An endophenotype is a heritable trait that is associated with a specific illness but is not a direct symptom of it. The presence or absence of such a trait is commonly taken to be an indication of whether an individual has the illness. Among several endophenotypes that have been linked with schizophrenia, the link for two in particular has seemed especially strong: abnormalities in eye movements and the inability to concentrate one's attention over sustained periods, sometimes called the inability to maintain vigilance.

Mark F. Lenzenweger, a professor of psychology at the State University of New York at Binghamton, has been working over the last several years to clarify the relationship between markers for schizophrenia and the presence or absence of the disease in individuals who display the markers. In the late 1990s, Lenzenweger was intrigued by data he had collected indicating that a widespread assumption about markers had never actually been proven in the laboratory.

"Deficits in eye tracking and attention span were thought to be a reflection of schizophrenia during the psychotic state," Lenzenweger explains, "but it wasn't known if the markers themselves would be predictive of the illness prior to its emergence."

Lenzenweger enlisted the help of Donald B. Rubin of Harvard University and Geoff McLachlan of the University of Queensland, Australia, statisticians renowned for their work with innovative mixture modeling techniques, to scrutinize laboratory measurements of the two markers taken from a group of 311 subjects who did not suffer from psychotic illness. The results, published in the Journal of Abnormal Psychology (vol 116, no.1), at once confirmed and confounded conventional wisdom.

With test results for all 311 subjects -- 61 percent female and ranging in age from 18 to 45 -- displayed in a single comprehensive table, "your eye could not have picked out where the break was," Lenzenweger says. "Yet within the total data set, two distinct groups emerged."

The larger of these groups, comprising 73% of the subjects, did not show evidence of deviations in either eye tracking or attention span. The remaining 27% of the subjects did, however, display clear deviations in one or both markers. This confirmed what Lenzenweger had suspected since the 1990s: that people who do not present clinical symptoms of schizophrenia may nevertheless have markers for the illness, and, perhaps, elevated risk for developing it at some point.

Lenzenweger is intrigued by the additional finding that some of the test subjects had first-degree biological relatives (a parent or sibling) who suffered from schizophrenia. Every one of these subjects was in the group that tested positive for aberrant eye tracking or attention span. Other test subjects had first-degree relatives with psychiatric illnesses other than schizophrenia, including bipolar disorder. Every one of these subjects was in the larger, "non-schizotypic" group.

Taken together, these findings bolster the hypothesis that the general population falls into one of two groups, one that has schizophrenia liability, and the other, much larger, that does not.

At the same time, they reveal for the first time that markers for the illness are present, if in dilute form, in people selected at random from the general population who do not actively suffer from the illness. Using a statistical technique called finite mixture modeling, Lenzenweger and colleagues have been able to assign a probability or risk value to each of the 300 subjects in their study. While none of the 300 has schizophrenia, each has a risk for the illness, ranging from nil in the larger group to substantive risk in the smaller group composed of those with "schizotypic" markers.

These risk predictions are not yet ready for clinical application, Lenzenweger cautions. He envisions using the new method to identify schizotypic individuals -- people at risk for the illness but who don't have it -- for more intense study. Specifically, he next wants to study the genomes of such individuals, to try to make the connection between the illness and variations in genes that have long been suspected to be deeply implicated in its causality.

"Schizophrenia has a large genetic component, as high as 80%, but it's a component that needs to be added to, in some ways, by environmental or what we call epigenetic factors," Lenzenweger says. Epigenetic factors affect gene expression and can determine what genes are turned on or turned off over the life-course.

By examining the genomes of people that his method identifies as normal but at elevated risk for schizophrenia, Lenzenweger hopes to get a step closer to the ultimate question of causality. "It's not enough to say someone's at risk. You want to say how or what put that person at risk: where in the brain this is happening, what systems are being disrupted. All the while, you keep working your way back to the DNA. Because ultimately, schizophrenia will be revealed to be a genetic illness with some degree of epigenetic component to it."

Solving this puzzle means doing what Lenzenweger calls "high-risk science," and that, he says, is "why I am so grateful for NARSAD's support. When you're doing things in science, you want to be free to do your most creative work, you want to be pushing the boundary. It's nice to know that an organization like NARSAD is out there that understands the importance of taking risks in science."

Source: NARSAD