Schizophrenia Not One Disease, New Genetic Evidence Shows

Megan Brooks

May 06, 2016

Schizophrenia is not a single disease but rather is a group of distinct subtypes with varying symptoms based on a set of genes harboring novel or rare disruptive variants, a new study suggests.

Researchers from New York University Langone Medical Center, in New York City, say they have uncovered mutations in four "influential" genes that clearly align with four different schizophrenia phenotypes, paving the way toward more personalized treatments. Patients with psychoses associated with mutations in each of the four genes differed from each other with respect to symptoms, intelligence level, and other disease features.

The study was published in the April issue of EBioMedicine.

Genes That Matter

"A large number of genes have been discovered that increase the vulnerability for psychiatric disorders, including schizophrenia," lead author Dolores Malaspina, MD, told Medscape Medical News. "They were found through large GWASs [genome-wide association studies], and they're not very specific. So the question is, how can we zero in on the genes that are likely to influence the disease more directly?" she explained.

"Our biologically driven study begins to answer long-standing questions in the field about why any two people diagnosed with schizophrenia may have drastically different symptoms. For the first time, we have defined four syndromes mechanistically," Dr Malaspina, the Anita Steckler and Joseph Steckler Professor in the Department of Psychiatry at NYU Langone, added in a news release.

The findings are based on an "exceptionally well-characterized" and ethnically diverse group of 48 individuals with psychosis for whom targeted exome sequencing was conducted with regard to four central nervous system signaling genes that have previously been shown to harbor disruptive de novo mutations in sporadic cases of schizophrenia. All four genes are involved in the growth or regulation of nerve circuits.

Fifteen of the 48 patients (31.25%) carried rare or novel variants in one or more of the four genes, and these subgroups of patients had significantly different symptoms.

One gene is PTPRG (receptor-type tyrosine-protein phosphatase gamma), which encodes a protein that allows nerve cells to connect as they form nerve networks. Patients with rare variants in this gene experienced earlier onset of relatively severe psychosis and had a history of learning disabilities. Despite high intelligence in some, they showed cognitive deficits in working memory, the researchers say.

Another influential gene is SLC39A13 (zinc transporter family 39 member 13). Patients with mutations in this gene also experienced early onset of schizophrenia, but they showed globally disrupted cognition and the most severe psychopathology, including negative symptoms and severe suicide attempts. They had the lowest intelligence and the least educational attainment, consistent with a developmental disorder, the researchers report.

Patients with variants in a third influential gene, ARMS/KIDINS220 (ankyrin repeat-rich membrane-spanning protein), showed early promise, and many attended college. They then experienced cognitive decline, consistent with a degenerative process.

Patients with variants in a fourth influential gene, TGM5 (transglutaminase 5), had less severe symptoms but often experienced attention-deficit disorder during childhood, and processing speed was slow in these patients.

Genotype, Then Treat?

"Our results argue that new treatments should ― while addressing core psychoses ― also focus on processing speed in TGM5 cases, working memory in PTPRG, zinc augmentation in SLC39A13, and nerve cell protection in patients with ARMS/KIDINS220 mutations," first study author Thorsten Kranz, PhD, a postdoctoral fellow at NYU Langone, said in the release. "Treatments that do not work for all patients may be highly effective in some."

For example, for patients with mutations in the zinc transporter SLC39A13, "there is a mouse model with a defect in this zinc transporter gene that has a behavior phenotype that is rescued by zinc supplementation, so we think this does set the stage to start carving out specific entities within the syndrome and specific treatments," Dr Malaspina told Medscape Medical News.

"Of course, this needs to be replicated in larger samples, but I think it sets the stage to better define the disease subtypes based on influential genes and not just the many, many hundreds of genes that subtly increase the variability for any number of psychiatric disorders," Dr Malaspina concluded.

This research was supported by the National Institutes of Health. The authors have disclosed no relevant financial relationships.

EBioMedicine. 2016;6:206-214. Full text


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