Four New Genetic Diseases Defined Within Schizophrenia

Changes in key genes clearly define four previously unknown conditions within the umbrella diagnosis of schizophrenia, according to a study led by researchers from NYU Langone Medical Center published online April 28 in EBioMedicine, a Lancet journal. Cases associated with changes in each of the four genes were different from each other in terms of symptoms, intelligence level and other disease features.

Unlike “big data” genetic studies, which have loosely linked hundreds of genetic changes to schizophrenia but cannot explain varying symptoms, the new study revealed distinct disease versions that may affect large slices of patients and enable precision treatment design, say the authors.

“A common fallacy is that schizophrenia can be treated as a single disease,” says NYU Langone psychiatrist and lead study author Dolores Malaspina, MD. “Our biologically driven study begins to answer longstanding 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.

“Perhaps as many as 30 percent of schizophrenic patients may now become candidates for more precise treatment based on the individual characteristics of these four genes, with the remaining cases becoming less mysterious as we pull these groups out of the mix,” says Malaspina, the Anita Steckler and Joseph Steckler Professor in the Department of Psychiatry at NYU Langone. “Our approach provides a new framework for finding influential genes across complex genetic diseases associated with paternal age, from schizophrenia to autism.”

Patients with schizophrenia struggle to interpret reality, typically suffering from hallucinations, learning disabilities, emotional withdrawal and lack of motivation. In the current study, researchers analyzed 48 ethnically diverse patients diagnosed with schizophrenia, looking at symptom sets in patients found to have rare or previously unknown changes in the DNA code of the four genes that disrupted brain function.

Key Genes Identified

The four influential genes now tied by the study to specific conditions are all involved in the growth or regulation of nerve circuits. They included PTPRG, which encodes a protein that enables nerve cells to connect as they form nerve networks. Patients with rare changes in this gene experienced earlier onset of relatively severe psychosis, and had a history of learning disabilities. Despite the high intelligence in some, they showed cognitive deficits in working memory, the “scratchpad” where the brain stores and processes temporary memories.

A second key gene, SLC39SA13, codes for a zinc transporter that helps nerve cells to “decide” whether or not nerve impulses are amplified of dampened. These cases showed widespread cognitive deficits, low educational attainment and the most severe deficits in emotion and motivation.

A third influential gene was ARMS/KIDINS220, which codes for a protein that regulates the growth of nerve cells. Patients who had changed versions of this gene showed early promise, often attending college, but then experienced cognitive decline consistent with a degenerative disease. The last gene of interest was TGM5, which encodes a protein that stabilizes protein groups. Related proteins have been linked to age-related degenerative conditions like Huntington’s disease. TGM5 cases had less severe symptoms, but were more often diagnosed with attention deficit disorder during childhood.

“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,” says first study author Thorsten Kranz, a postdoctoral fellow in the lab of NYU Langone neuroscientist Moses Chao, PhD. “Treatments that do not work for all patients may be highly effective in some.”

Image shows a DNA double helix.
Unlike “big data” genetic studies, which have loosely linked hundreds of genetic changes to schizophrenia but cannot explain varying symptoms, the new study revealed distinct disease versions that may affect large slices of patients and enable precision treatment design, say the authors. Image is for illustrative purposes only.

A study published last year by the same team lay the foundation for the current EBioMedicine publication by defining the framework for finding influential genes. This study examined the genetic code of affected patients with schizophrenia and their healthy parents to identify newly occurring (sporadic) mutations that disrupted the four influential signaling genes in 31 percent of these patients.

In general, more than 70 percent of schizophrenia cases are sporadic versus familial – so many patients have variants of influential genes that have occurred in them for the first time. Malaspina’s team was the first to show in a 2001 paper that the most important source of these rare, sporadic changes was the paternal germline (father’s sperm), with advanced paternal age explaining over a quarter of the population risk for schizophrenia in an Israeli cohort. Sperm cells divide and multiply 600 times by the time a father reaches age 50. DNA is copied with each round of cell divisions, and copy errors accumulate as a father ages.

“Our combined findings to date argue that newly occurring mutations introduced via the father’s germline in sporadic cases, when compared to healthy parents, represent a powerful tool for defining precise versions of schizophrenia,” says Malaspina.

About this genetics research

Along with Malaspina, the study was led by Kranz and Chao of the Skirball Institute of Biomolecular Medicine, Departments of Cell Biology, Physiology & Neuroscience and Psychiatry, at NYU Langone, and by medical students Adam Berns and Jerry Shields of the Institute for Social and Psychiatric Initiatives (InSPIRES), Department of Psychiatry, New York University School of Medicine. Other study authors were Julie Walsh-Messinger of the University of Dayton Department of Psychology and Raymond Goetz of the New York State Psychiatric Institute, Division of Clinical Phenomenology.

Funding: This work was supported by the National Institutes of Health grants RC1-MH088843, K24-MH001699, NYU CTSI UL1TR000038, and R01-MH086651.

Source: Greg Williams – NYU Langone Medical Center
Image Credit: The image is in the public domain.
Original Research: Full open access research for “Phenotypically distinct subtypes of psychosis accompany novel or rare variants in four different signaling genes” by Thorsten M. Kranz, Adam Berns, Jerry Shields, Karen Rothman, Julie Walsh-Messinger, Raymond R. Goetz, Moses V. Chao, and Dolores Malaspina in EBioMedicine. Published online March 21 2016 doi:10.1016/j.ebiom.2016.03.008


Abstract

Phenotypically distinct subtypes of psychosis accompany novel or rare variants in four different signaling genes

Background
Rare gene variants are important sources of schizophrenia vulnerability that likely interact with polygenic susceptibility loci. This study examined if novel or rare missense coding variants in any of four different signaling genes in sporadic schizophrenia cases were associated with clinical phenotypes in an exceptionally well-characterized sample.

Method
Structured interviews, cognition, symptoms and life course features were assessed in 48 ethnically-diverse cases with psychosis who underwent targeted exome sequencing of PTPRG (Protein Tyrosine Phosphatase, Receptor Type G), SLC39A13 (Solute Carrier Family 39 (Zinc Transporter) Member 13), TGM5 (transglutaminase 5) and ARMS/KIDINS220 (Ankyrin repeat-rich membrane spanning protein or Kinase D-Interacting Substrate of 220 kDa). Cases harboring rare missense coding polymorphisms or novel mutations in one or more of these genes were compared to other cases not carrying any rare missense coding polymorphisms or novel mutations in these genes and healthy controls.

Findings
Fifteen of 48 cases (31.25%) carried rare or novel missense coding variants in one or more of these genes. The subgroups significantly differed in important features, including specific working memory deficits for PTPRG (n = 5); severe negative symptoms, global cognitive deficits and poor educational attainment, suggesting a developmental disorder, for SLC39A13 (n = 4); slow processing speed, childhood attention deficit disorder and milder symptoms for TGM5 (n = 4); and global cognitive deficits with good educational attainment suggesting neurodegeneration for ARMS/KIDINS220 (n = 5). Case vignettes are included in the appendix.

Interpretation
Genes prone to missense coding polymorphisms and/or mutations in sporadic cases may highlight influential genes for psychosis and illuminate heterogeneous pathways to schizophrenia. Ethnicity appears less important at the level of genetic variability. The sequence variations that potentially alter the function of specific genes or their signaling partners may contribute to particular subtypes of psychosis. This approach may be applicable to other complex disorders.

“Phenotypically distinct subtypes of psychosis accompany novel or rare variants in four different signaling genes” by Thorsten M. Kranz, Adam Berns, Jerry Shields, Karen Rothman, Julie Walsh-Messinger, Raymond R. Goetz, Moses V. Chao, and Dolores Malaspina in EBioMedicine. Published online March 21 2016 doi:10.1016/j.ebiom.2016.03.008

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