Candidate Genes Implicated in Schizophrenia

Jacquelyn K. Beals, PhD

October 24, 2008

October 24, 2008 — A Dutch study of copy number variations (CNVs) has identified at least 3 candidate genes for schizophrenia susceptibility, according to an October 10 report in the American Journal of Human Genetics. The genes are involved in the function, migration, and adhesion of neurons and are expressed highly in brain relative to comparison tissues.

Dutch patients in the initial genome-wide screen (n = 54) were diagnosed with "deficit schizophrenia," a severe form of the illness with persisting negative symptoms. Initial results identified 90 CNVs, of which 77 had been previously found in a nonschizophrenic population (n = 270). The 13 remaining CNVs were also absent from the authors' genome-wide studies of patients with idiopathic mental retardation (n > 1300). Each of these 13 CNVs was detected in only 1 schizophrenic patient.

Among these CNVs, 7 did not affect a gene and were located in poorly conserved genomic regions (ie, regions with frequent genetic variations). Guided by gene content, the investigators focused on 4 CNVs that disrupted genes associated with neural function or development:

  • deletion affecting nrxn1, located on chromosome 2;

  • deletion affecting astn2, located on chromosome 9;

  • duplication disrupting myt1l, located at the breakpoint on chromosome 2;

  • duplication disrupting ctnnd2, located at the breakpoint on chromosome 5.

Medscape Pathology & Lab Medicine heard via email from Roel A. Ophoff, PhD, a coauthor of the study. Regarding nrxn1, he mentioned several papers showing that "disruptions of this gene (either through deletions or duplications) are involved in autism and schizophrenia. It is not so much that 2 copies of the gene are problematic, as far as we can tell at the moment, but that disruption of the coding sequence is causation of psychiatric traits."

Dr. Ophoff is assistant professor in the Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California at Los Angeles, and is on the faculty of the Rudolf Magnus Institute of Neuroscience and the Department of Medical Genetics, University Medical Center, Utrecht, the Netherlands

The 4 CNV regions were further studied in individuals of Dutch descent with various types of schizophrenia (n = 752) and control patients (n = 706). CNVs were found in the candidate regions in 7 schizophrenic patients and 1 control patient: 4 patient CNVs were in nrxn1, 2 patient CNVs were in the region of myt1l, and 1 duplication affected astn2 and a nearby gene. The CNV in the control individual was a duplication within nrxn1.

Overall, CNVs in nrxn1 made up 5 of the 11 patient CNVs (within the 4 candidate regions) in this study. Earlier studies associated deletions in this gene with schizophrenia, autism, or mental retardation.

CNVs in myt1l made up 3 of the 11 patient CNVs. myt1l belongs to the family myelin transcription factor 1, which is responsible for regulating the formation and differentiation of glial cells that form myelin within the central nervous system.

The gene astn2 is expressed at high levels within the brain but is not well understood. A homologous gene (astn) is involved in migration of nerve cells during development. Finally, a CNV in ctnnd2 was detected in only 1 patient, suggesting that variation in this area may be pathogenic. ctnnd2 "is located in the critical region for autism spectrum disorder...and mental retardation in cri du chat syndrome," according to the article.

Dr. Ophoff commented on the association between autism and at least 2 regions highlighted in this study. "[N]ot only do we see increasing evidence of a link between autism and schizophrenia, but also that other 'brain diseases' might havea common pathway," he said. "If so, I think that we are dealing with a general imbalance of the brain development. Alternatively [in deletions], we should consider the other nondeleted allele and perhaps discover that specific variants on that chromosome are predisposing to these diseases."

Medscape Pathology & Lab Medicine also received email commentary from David A. Collier, PhD, from the Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College, London, United Kingdom. "There is evidence that the same CNVs can give rise to a range of phenotypes: autism, schizophrenia, mental handicap. This indicates partial etiological overlap [between these diseases]. It may be that there is some disruption of the brain that can give rise to a variety of disorders," he concluded.

The authors advise caution when differentiating between CNVs that affect genes and those affecting intervening sequences. "We know most about coding genes, and that disruption can lead to (congenital) disease traits," said Dr. Ophoff. "For that reason, we will always focus on CNVs affecting genes. In the case of schizophrenia, we focus on disrupted genes that are expressed in the brain."

He further noted, "One challenge which we face is that 'healthy' control subjects harbor unique CNVs as well. We need to be able to distinguish between disease-associated [CNVs] and those that are [not]. To make this clinically relevant, we need to join forces in the field, perhaps across nosological boundaries, to increase sample size and provide the genetic evidence that these CNVs are really involved," Dr. Ophoff said.

"I expect that in the near future we will have a list of CNVs that dramatically increase the risk of developing a psychiatric trait.... However, before we will clinically apply these steps," said Dr. Ophoff," we first need to examine the phenotypes of patients with these CNVs more carefully, study the parents, obtain insight whether the CNVs are inherited or have occurred de novo. That is something we are currently doing."

Dr. Ophoff and Dr. Collier have disclosed no relevant financial relationships.

Am J Human Genet. 2008;83:1—7.


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