Altered gene synchrony suggests a combined hormone-mediated dysregulated state in major depression

Abstract

Coordinated gene transcript levels across tissues (denoted "gene synchrony") reflect converging influences of genetic, biochemical and environmental factors; hence they are informative of the biological state of an individual. So could brain gene synchrony also integrate the multiple factors engaged in neuropsychiatric disorders and reveal underlying pathologies? Using bootstrapped Pearson correlation for transcript levels for the same genes across distinct brain areas, we report robust gene transcript synchrony between the amygdala and cingulate cortex in the human postmortem brain of normal control subjects (n = 14; Control/Permutated data, p<0.000001). Coordinated expression was confirmed across distinct prefrontal cortex areas in a separate cohort (n = 19 subjects) and affected different gene sets, potentially reflecting regional network- and function-dependent transcriptional programs. Genewise regional transcript coordination was independent of age-related changes and array technical parameters. Robust shifts in amygdala-cingulate gene synchrony were observed in subjects with major depressive disorder (MDD, denoted here "depression") (n = 14; MDD/Permutated data, p<0.000001), significantly affecting between 100 and 250 individual genes (10-30% false discovery rate). Biological networks and signal transduction pathways corresponding to the identified gene set suggested putative dysregulated functions for several hormone-type factors previously implicated in depression (insulin, interleukin-1, thyroid hormone, estradiol and glucocorticoids; p<0.01 for association with depression-related networks). In summary, we showed that coordinated gene expression across brain areas may represent a novel molecular probe for brain structure/function that is sensitive to disease condition, suggesting the presence of a distinct and integrated hormone-mediated corticolimbic homeostatic, although maladaptive and pathological, state in major depression.

Figure 1. Correlated genewise transcript levels across brain regions.

A–D Examples of within-subject positive, negative and absent amygdala-cingulate gene synchrony. E The right-shifted histogram of genewise transcript correlation suggests that the majority of genes are similarly regulated in both areas. The permutated data (dashed line) is centered on zero, indicating that gene coordination is subject-specific. F A similar pattern of gene synchrony was observed between two areas of the prefrontal cortex in an independent cohort (“BA”, Brodman area). G The lack of correlations in the extent of gene synchrony between the amygdala-cingulate and prefrontal cortical areas demonstrate that different sets of genes present coordinated transcript levels in the two different sets of brain areas (G, R = 0.002). AMY, amygdala, ACC, anterior cingulate cortex.

Figure 2. Age-related genes do not significantly influence gene coordination.

A Age-detrended bootstrapped estimates of gene coordination were significantly different from the null permutated model (p<.00001; distribution outlined by black dashed line) and did not decrease the overall levels of gene coordination, when compared to the original bootstrap estimates (red distribution). B–C Relationships between amygdala-cingulate coordination and age correlation, before (B) and after (C) removal of any age-correlation indicated that age-detrending did not affect amygdala-cingulate regional coordination. As shown in C, the distribution of age correlations is centered on zero and highly compressed compared to figure B. The residual spread in the y-axis is due to inevitable, small, randomly occurring correlations while resampling the detrended data. D Histogram of correlations between original and detrended amygdala-cingulate coordination levels, showing that the vast majority of genes retain highly similar regional correlation, thus demonstrating an overall very small contribution of age to regional gene synchrony.

Figure 3. Altered amygdala-cingulate regional gene synchrony in subject with major depression.

A Global right-shifted histogram of gene synchrony in subjects affected with depression. B Comparing gene synchrony between control and depressed subjects confirmed that genes are similarly regulated in both groups (Gray dots) and identified numerous genes with robust decrease (Blue dots: High R in controls, low R in depression) or increase (Red dots: low R in controls, high R in depression) in amygdala-cingulate synchrony. C Single gene examples. D The top genes and molecule interaction networks built on genes selected with increased (right) or decreased (left) amygdala-cingulate synchrony in depression share similarities in signal transduction components and were linked through insulin, a homeostatic modulator with significant links to both networks ( Table 1 ). IL1 was significantly connected to the network build in genes with increased regional synchrony in depression. Grey, depression-affected genes; White, genes or bioactive molecules significantly connected to the network.