This is another good postmortem study from the Haroutunian laboratory. Although the studies are somewhat limited in scope and the conclusions are quite speculative (linking genetic, clinical, and cognitive disturbances to the dysfunction of the node of Ranvier), they are still a breeze of fresh air in schizophrenia research. They offer a new explanation of myelination deficits in schizophrenia, linking it to genetics and disturbed connectivity across the brain regions. We need such new hypotheses, new ideas. Is this one correct? It is certainly plausible, and supported by some data. However, if the past is a predictor of the future, we can be almost certain that the answer will be much more complicated than we think.

View all comments by Karoly Mirnics

Roussos and colleagues conducted a study that, in part, follows up findings from large-scale genetic association studies.

They hypothesized that there is a failure in saltatory conduction in schizophrenia and therefore potential dysfunction in the nodes of Ranvier (NOR) in schizophrenia. To evaluate this hypothesis, they performed microarray transcription analysis on multiple cortical regions in postmortem brain tissue from schizophrenia patients and controls. They selectively analyzed these transcriptome data for changes in genes which play a role in the NOR. They state that they identified dysregulation of genes known to be involved in development, organization, and maintenance of NOR across multiple brain regions. They were able to validate four of the genes using quantitative PCR, and to verify that these genes were not altered in brains of rats treated with haloperidol (i.e., less likely to be an effect of drug treatment).

Given the association of ANK3 in bipolar disorder, some evidence of association in schizophrenia, and the evidence of etiological overlap between the disorders, they decided to follow up specifically on ANK3. They looked at whether genetic variants in ANK3 showed any functional effects. Their findings indicated that rs9804190 had expression changes in schizophrenia patients, but not controls, and a weak but consistent genetic association with disease in a small sample. They also demonstrated an association of the rs9804190*C with differences in performance on neurocognition, personality, and fMRI activation in the frontal gyrus in unaffected individuals.

The tests of their major hypothesis of NOR dysfunction in schizophrenia were indirect, and the findings somewhat equivocal (few genes were significantly altered in their findings, and their handling of multiple testing was worrying). However, given the previous evidence for ANK3 in psychiatric disease and its role as a key player in NOR function, Roussos et al. followed up on an intriguing and potentially important risk factor and delved into multiple levels of functional evidence. While ANK3 has certainly shown more evidence of association in bipolar disease than in schizophrenia, the choice of this gene for follow-up is sensible, given the evidence of etiological overlap between these two diseases.

Additionally, this level of functional work will be critical to future understanding of the role that individual risk factors play in psychiatric disease. The authors consistently found evidence for functional effects of one SNP, rs9804190. Either the C allele or CC homozygotes showed functional or genetic effects in each of the experiments. However, several of these tests did not directly pertain to schizophrenia; their genetic findings for schizophrenia were weak and from a small sample set; there were functional findings in healthy individuals, despite the lack of findings of expression changes in controls (which could be due to lack of power); and it is unclear whether this SNP is truly functional or simply in high LD with a functional variant. Nonetheless, it seems clear that either this variant or a variant in high LD may have a functional effect on ANK3 and specific brain functions. While the support of overall NOR dysfunction was not conclusive, the findings are consistent with ANK3 as an intriguing candidate for contributions to the etiology of psychiatric disease.

View all comments by Patrick Sullivan
View all comments by Ann Collins