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Converging on Genes for Schizophrenia

Data from animals, humans, autopsies, and electrophysiology identify a variant potassium-channel gene and suggest its role in a core feature of schizophrenia.

Researchers have not identified a causative gene for schizophrenia, a group of disorders with complex interactions between genetically and epigenetically influenced traits. Unlike most studies using single lines of investigation, this landmark series of experiments used data on animals, humans, autopsies, and electrophysiology that converged on a core feature of schizophrenia.

First, the researchers studied single nucleotide polymorphisms (SNPs) in 10 candidate genes in 170 European families with offspring who had schizophrenia. The most robust association with schizophrenia risk was in a region in chromosome 7 that codes for the voltage-activated delayed-rectifier potassium channel KCNH2. In healthy unrelated subjects, three KCNH2 SNPs were significantly associated with:

• Lower IQ and slower information-processing speed (cognitive findings previously associated with genetic risk for schizophrenia in discordant twins)
  
• Smaller hippocampal volume on MRI
  
• On functional MRI, greater hippocampal activation (indicating inefficient memory processing) during a memory test and inefficient processing in the dorsolateral prefrontal cortex (DLPFC) during an executive-function test
  

In a postmortem study, KCNH2 mRNA expression was lower in the DLPFC and hippocampus of schizophrenia patients than of controls. This finding might be independent of medication effects: In rats, chronic exposure to antipsychotic drugs did not alter KCNH2 expression.

A KCNH2 variant (KCNH2-3.1), a brain-specific primate gene, had hippocampal mRNA expression that was greater in schizophrenia patients than in controls and was associated with the risk SNPs. In brain samples, KCNH2-3.1 expression increased prenatally and then decreased after birth. In transfected neurons, KCNH2-3.1 overexpression was associated with decreased activation and faster deactivation of the rectifier potassium current, resulting in a high-frequency and nonadaptive pattern of neuronal firing.

Comment: An editorialist notes the unique specificity and breadth of these studies. The researchers used multiple experimental paradigms to identify and characterize a variant potassium-channel gene associated with schizophrenia and with information-processing disturbances in normal people. The variant is specific to primates and appears to interfere with cognition by altering neuronal repolarization, resulting in excessive neuronal firing that decreases the signal-to-noise ratio. This might contribute to defective gating of information, a core cognitive deficit of schizophrenia, which clinically manifests as an inability to discriminate between relevant and irrelevant social and psychological data. Normal people with this deficit might be socially and cognitively odd (e.g., schizotypal or schizoid); those who are also vulnerable to psychosis might develop schizophrenia. Eventually, specific brain KCNH2-3.1 blockers might normalize information processing without producing QT prolongation from the blockade of potassium efflux channels in the heart.

— Steven Dubovsky, MD

Published in Journal Watch Psychiatry July 13, 2009

Citation(s):

Huffaker SJ et al. A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia. Nat Med 2009 May; 15:509.

• Medline abstract (Free)

Horváth S and Mirnics K. Breaking the gene barrier in schizophrenia. Nat Med 2009 May; 15:488.

• Medline abstract (Free)