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Schizophrenia-associated Variant in ZNF804A Gene Affects Brain Connectivity

5 May 2009. A short report in the May 1 issue of Science links a genetic variant recently tied to psychosis to a brain phenotype of altered functional connectivity during two different memory tasks in healthy individuals. The work, from the lab of Andreas Meyer-Lindenberg of the University of Heidelberg in Mannheim, Germany, shows that the psychosis-linked single-nucleotide polymorphism (SNP) in the ZNF804A gene is associated with alterations in the coordinated activity of the dorsolateral prefrontal cortex (DLPFC) and other brain regions. The work suggests that variants of ZNF804A, a zinc finger protein of unknown function, may contribute to the risk of schizophrenia and bipolar disorder via their influence on specific brain networks.

The rs1344706 SNP in the ZNF804A gene was identified in the largest-to-date genomewide association and replication study for schizophrenia and bipolar disorder, which covered over 20,000 patients and controls and was published last summer (see SRF related news story). To try to connect the dots between SNP variants and a brain phenotype, first authors Christine Esslinger of the University of Heidelberg and Henrik Walter of the University of Bonn, Germany, genotyped 115 healthy Germans for rs1344706, and then measured brain activation by fMRI during two memory tasks. They used the n-back test of working memory because it elicits activation of the DLPFC, whose function is altered in schizophrenia, and whose activity is affected by variation in other genes linked to schizophrenia (Meyer-Lindenberg and Weinberger, 2006). The researchers measured the simultaneous changes in BOLD signals in different regions of the brain, an indication of functional connectivity. The results show that people carrying the schizophrenia-associated allele had altered connectivity between the dorsolateral prefrontal cortex and the hippocampus during the n-back test. In a face recognition test, which engages the hippocampus and the amygdala, they also found differences in connectivity that were significantly associated with genotype.

In contrast to the imaging measures, the variants had no discernable effect at the level of behavior, as genotype was not associated with performance on the memory tasks. This is consistent with the idea that the connectivity alterations are a proximal effect of the genetic variations, and so may represent an intermediate phenotype that relates to disease. Alterations in DLPFC function have been proposed to be a hallmark of schizophrenia, but the variations in amygdala connective may relate more to bipolar disorder, the authors suggest.

Abnormal coupling between the DLPFC and hippocampus, as well as other networks, have been identified in schizophrenia patients and in their at-risk relatives (for a recent example, see SRF related news story). The current study goes a step further in identifying a potential genetic contributor to connectivity. Much work remains to pin down the exact alleles responsible for the observed effects, but the authors argue that the work validates the use of intermediate phenotypes to study the genetics of complex psychiatric diseases by showing that “mechanisms underlying genetic findings supported by genome-wide association are highly penetrant in brain, agree with the pathophysiology of overt disease, and mirror candidate gene effects.” The results warrant further study on the possible role of the ZNF804A protein in development or function of the suspect networks, they write.—Pat McCaffrey.

Reference:
Esslinger C, Walter H, Kirsch P, Erk S, Schnell K, Arnold C, Haddad L, Mier D, Opitz von Boberfeld C, Raab K, Witt SH, Rietschel M, Cichon S, Meyer-Lindenberg A. Neural mechanisms of a genome-wide supported psychosis variant. Science. 2009 May 1;324(5927):605. Abstract

 
Comments on News and Primary Papers
Comment by:  James WaltersMichael Owen (SRF Advisor)
Submitted 3 June 2009 Posted 3 June 2009

Andreas Meyer-Lindenberg’s group examine the association between a single nucleotide polymorphism (SNP), rs1344706 in gene ZNF804A, recently identified as a risk factor for schizophrenia in a genome-wide association study (GWAS) (O'Donovan et al., 2008) and functional connectivity as measured by fMRI. The attraction of this polymorphism for a study of this kind is twofold. First, statistically speaking it is the most robust SNP association with schizophrenia reported to date. Second, because a single variant shows strong evidence for association, which is not the case for other reported associations, it is possible to specify a priori for the gene in question directional hypotheses in relation to potential neurocognitive correlates. This militates against the generation of false positives through the testing of multiple SNPs and haplotypes which has rendered problematic the interpretation of at least some previous genetic imaging studies (Walters and Owen, 2007). The function...  Read more


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