June 26, 2014. Genes suspected in schizophrenia impinge upon a specific connection in the brain, according to a study published June 16 in the Proceedings of the National Academy of Sciences. A team led by Andreas Meyer-Lindenberg, Heike Tost, and Luanna Dixson, all from the University of Heidelberg, Mannheim, Germany, scanned the brains of 269 healthy people to measure the activation in the hippocampus, a region important for memory, and the dorsolateral prefrontal cortex (DLPFC), a region responsible for executive functions. The degree of hippocampal-DLPFC coupling was associated with genes involved in synapse development and plasticity, which agrees with recent genetic studies of schizophrenia.
The findings suggest that genetic risk factors for schizophrenia somehow warp connectivity in the brain and compromise their plasticity. The study used gene set analysis to see if the genetic variants that correlated with brain imaging findings also converged on certain categories of genes, grouped according to their function. This approach has been enlisted before in attempts to find common biological pathways for the diverse lot of variants turning up in genetic studies of schizophrenia (see SRF related news report; SRF news report).
The new study applies this approach to HC-DLPFC coupling, an intermediate phenotype relevant to schizophrenia. The HC-DLPFC circuit is typically enlisted during working memory tasks, which require a person to keep in mind multiple items before giving an answer. HC-DLPFC coupling and working memory are impaired in people with schizophrenia (Meyer-Lindenberg et al., 2005) and their unaffected relatives (Erk et al., 2013), and may be a core deficit of this disorder. Intermediate phenotypes are postulated to have a closer relationship to genes than the heterogeneous behavioral symptoms that define the disorder; thus, the genes underpinning working memory may be relevant for schizophrenia as well.
Enriched for synapses
Applying gene set analysis to functional magnetic resonance imaging results involved several steps. First author Luanna Dixson and colleagues began by imaging the brains of healthy people performing a working memory task. As expected, the researchers found negative functional connectivity between HC and DLPFC, meaning that when the right DLPFC was activated, the left HC activity was suppressed.
The researchers next genotyped each study participant’s DNA at nearly half a million single nucleotide polymorphisms (SNPs) and associated each with the degree of HC-DLPFC coupling, thus obtaining a p value for each SNP. Each SNP, regardless of p value, was then mapped to a nearby gene, and the lowest p value for that gene was taken for gene set analysis. This involved assigning each gene to one of several gene sets categorized by their biological processes, as annotated by the Molecular Signatures Database. An enrichment score for each gene set was calculated that reflected how well the gene set correlated with HC-DLPFC coupling.
The end result pointed to significant enrichment in the “synapse organization and biosynthesis” category of genes. This category contains several genes with some proposed link to schizophrenia: CACNB2, highlighted as a hit in the most recent schizophrenia GWAS (see SRF related news report); neuroligin 1 (NLGN1), a receptor for neurexin, which has turned up in rare variant studies of schizophrenia; neural cell adhesion molecule (NRCAM), which has been highlighted as a gene of interest in Korean studies of schizophrenia (Kim et al., 2009); and ubiquitin B (UBB), which tags proteins for removal but may also have a hand in synapse formation and maintenance, processes that may be disrupted in schizophrenia (Bousman et al., 2010). Several protocadherin genes, which encode adhesion molecules that act in the developing brain, perhaps specifically at synapses, also belonged to this gene set.
Ultimately, the importance of this enrichment depends on how valid the original gene set groupings are, which is something that’s bound to shift as more functional annotations for each gene roll in. In the meantime, the findings offer a circuit-level understanding of gene action and suggest that risk variants for schizophrenia make this circuit in the brain more vulnerable early in life to adverse experiences that may come later.—Michele Solis.
Dixson L, Walter H, Schneider M, Erk S, Schäfer A, Haddad L, Grimm O, Mattheisen M, Nöthen MM, Cichon S, Witt SH, Rietschel M, Mohnke S, Seiferth N, Heinz A, Tost H, Meyer-Lindenberg A. Identification of gene ontologies linked to prefrontal-hippocampal functional coupling in the human brain. PNAS 2014; published ahead of print June 16, 2014.