Converging genetic and functional brain imaging evidence links neuronal excitability to working memory, psychiatric disease, and brain activity

Abstract

Working memory, the capacity of actively maintaining task-relevant information during a cognitive task, is a heritable trait. Working memory deficits are characteristic for many psychiatric disorders. We performed genome-wide gene set enrichment analyses in multiple independent data sets of young and aged cognitively healthy subjects (n = 2,824) and in a large schizophrenia case-control sample (n = 32,143). The voltage-gated cation channel activity gene set, consisting of genes related to neuronal excitability, was robustly linked to performance in working memory-related tasks across ages and to schizophrenia. Functional brain imaging in 707 healthy participants linked this gene set also to working memory-related activity in the parietal cortex and the cerebellum. Gene set analyses may help to dissect the molecular underpinnings of cognitive dimensions, brain activity, and psychopathology.

Figure 1

Manhattan plot of the GWAS in the discovery sample. The red horizontal line indicates genome-wide Bonferroni correction.

Figure 2

Visualization of each significant SNP’s percent contribution (in descending order) to the overall significance of the voltage-gated cation channel activity gene set in the discovery sample.

Figure 3

Parietal activity related to working memory independent of genotype. Color-coded t values (P_{whole-brain -FWE-corrected} < 0.05; n=707). The map is centered at [-17 -66 52] in the left superior parietal cortex. Activations are overlaid on coronal (upper left), sagital (upper right) and axial (lower left) sections of the study specific group template (see Experimental procedure). L, left side of the brain; R, right side of the brain.

Figure 4

Cerebellar activity related to working memory independent of genotype. Color-coded t values (P_{whole-brain-FWE-corrected} < 0.05; n=707). The map is centered at [14 -55 -48] to illustrate activations in the cerebellum. Activations are overlaid on coronal (upper left), sagital (upper right) and axial (lower left) sections of the study specific group template (see Experimental procedure). L, left side of the brain; R, right side of the brain.

Figure 5

Genetic score-dependent increases in WM-related brain activity (n=707). The blue circles show the activation in (A) the left parietal cortex and (B) the right cerebellum. The maximum is located at [-16.5 -66 52] in the left superior parietal cortex; t = 5.04, P_{whole-brain-FWE-corrected} = 0.0063, P_uncorrected = 5.9×10^-7. The local maximum in the cerebellar cortex is located at [13.75 -55 -48]; t = 4.55, P_{whole-brain-FWE-corrected} = 0.049, P_uncorrected = 6.31×10^-6. Activations are overlaid on coronal (upper left), sagital (upper right) and axial (lower left) sections of the study specific group template (see Experimental Procedures); displayed at P_uncorrected = 0.001, using color-coded t values. L, left side of the brain; R, right side of the brain.