February 25, 2014. Working memory stems in part from genes encoding voltage-gated cation channels, according to a paper published online February 13 in Neuron. Led by Andreas Papassotiropoulos of the University of Basel, Switzerland, the study uses gene set analysis to find biological themes among common genetic variants associated with working memory. Voltage-gated cation channels turned up in multiple, independent samples, including one consisting of people with schizophrenia, which is marked by working memory impairment.
The new study complements genetic findings implicating voltage-gated calcium channel genes in schizophrenia (see SRF related conference report) and bipolar disorder (see SRF related news report). This suggests that the way neurons process information they receive is perturbed in psychiatric disorders—a different kind of pathology from the suspected faulty transfer of information between neurons based on links to genes for synaptic machinery (e.g., see SRF related news report).
The study also grapples with the problem of how to make sense of the rising number of genes associated with different conditions or traits as studies grow larger. Researchers have developed methods to group genes according to their functions and then ask whether a particular gene set is hit hard in a disorder. At the moment, however, a kind of Wild West of tools exists, making it difficult to gauge the replicability of any one result based on gene set analysis. The new study addresses this by putting its gene set analysis method to the test in multiple samples—from young, healthy people; elderly, non-demented people; people with schizophrenia; and in brain imaging data.
First authors Angela Heck and Matthias Fastenrath began by looking for single nucleotide polymorphisms (SNPs) associated with working memory in a sample of 905 healthy, young adults. Their working memory was tested with the n-back task, in which participants are presented with a series of letters and asked to indicate whether the current letter matches the one shown two letters prior. This classic test of working memory involves remembering the sequence of letters and updating and manipulating that information.
A genomewide association study (GWAS) of performance on the n-back task turned up five SNPs that reached genomewide significance. But rather than focusing on the few genes with significant p values, the gene set analysis method, called MAGENTA, took a gene-centered approach by assigning for each gene the lowest p value obtained by any SNP within that gene in the GWAS. It then asked whether certain pre-defined gene sets were enriched for low p values compared to a random gene set.
The answer was yes for the voltage-gated cation channel activity gene set, as defined by the Gene Ontology database, which groups genes according to what is known about their function. This included multiple subunits of voltage-gated calcium channels such as CACNA1A, potassium channels, and sodium channels. This finding was replicated in an independent sample of 746 people tested, and analyzing the combined sample with two other gene set algorithms also found significant enrichment for the same gene set. Though working memory declines with age, significant enrichment in this gene set was detected in 763 elderly people evaluated with a different test of working memory, though this did not survive genomewide correction.
Because working memory is impaired in schizophrenia, the researchers tested whether this same gene set would be implicated by SNPs associated with risk for schizophrenia by GWAS. Using data from 32,143 individuals in the Psychiatric Genomics Consortium’s case-control samples (see SRF related news report), they again found enrichment for this voltage-gated cation channel activity gene set.
Overall, the results suggest that the ion channels controlling the excitability of a neuron contribute to the sustained neural activity thought to mediate working memory. To directly capture the influence of this particular gene set on brain activity, the researchers imaged 707 people from their young, healthy sample while they performed the n-back task. The researchers then calculated a gene set score for each individual based on their SNPs; this score reflected the genetic load of working memory-associated alleles within the voltage-gated ion channel gene set. Plotting this score against brain activity revealed positive correlations within the superior parietal cortex and the cerebellum—something that reinforces the idea that the cerebellum performs more than motor coordination (see SRF related news report). This relationship seemed specific to working memory, because no significant correlations emerged when brain activity during an episodic memory task was used instead.
This kind of analysis may reveal the contributions of other gene sets to other kinds of brain activity and provide a more deconstructed look at a heterogeneous disorder such as schizophrenia. Though the ion channel gene set found here suggests targets for drug development, manipulating such integral components of a neuron’s function may be tricky.—Michele Solis.
Heck A, Fastenrath M, Ackermann S, Auschra B, Bickel H, Coynel D, Gschwind L, Jessen F, Kaduszkiewicz H, Maier W, Milnik A, Pentzek M, Riedel-Heller SG, Ripke S, Spalek K, Sullivan P, Vogler C, Wagner M, Weyerer S, Wolfsgruber S, de Quervain DJ, Papassotiropoulos A. Converging Genetic and Functional Brain Imaging Evidence Links Neuronal Excitability to Working Memory, Psychiatric Disease, and Brain Activity. Neuron. 2014 Feb 13. Abstract