Genetics of the HPA-Axis Predict Limbic Connectivity Patterns

Sudheimer K, Keller J, O'Hara R, Hantke N, Karna R, Duvio D, Beaudreau S, Heinemeyer E, Reiss A, Murphy G, Gomez R, Garrett A, Tennakoon L, Schatzberg AF
American College of Neuropsychopharmacology. 2016.


Background: Dysregulation of limbic brain networks and dysregulation of the HPA-axis are both considered likely contributing factors to the development and maintenance of emotional symptoms in depression. Our group has shown that HPA-axis signaling plays are role in modulating the activity and connectivity of limbic structures. This work demonstrates how HPA-axis genetic polymorphisms that affect ligand-receptor interactions have effects on large-scale patterns of limbic connectivity.
Methods: This study uses an array of naturally occurring single nucleotide polymorphisms (SNPs) of HPA-axis genes (corticotropin releasing hormone, and corticotropin releasing hormone receptors 1 & 2, glucocorticoid receptor, mineralcorticoid receptor), age, gender, and severity of depressive symptoms to predict large scale patterns of resting state limbic functional connectivity in a mixed group of healthy participants and depressed patients. Limbic functional connectivity was assessed using a combination of 1) a novel hierarchical clustering approach to reduce non-homogenous time-courses within 2) an anatomical seed-based simple-regression approach. All predictive models were adjusted for multiple comparisons. These analyses do not use the cluster-level inference approach that has recently been shown to be particularly vulnerable to type- 1 error.
Results: Depressive symptoms in combination with a variety of HPA-axis SNPs were able to predict limbic connectivity with the subgenual cingulate (Brodmann Area 25), the putamen and the thalamus. Independent of depressive symptoms different combination of HPA-axis SNPs were also able to predict limbic connectivity to a variety of other brain regions including the amygdala, caudate, middle cingulate cortex, posterior cingulate cortex, claustrum, hippocampus, hypothalamus, midbrain, pallidum, parahippocampal cortex, pons, and brainstem.
Conclusions: This study suggests that the limbic connectivity of the subgenual cingulate (BA25), putamen, and thalamus may play a critical role in depression pathophysiology. It also suggests a prominent role for neuroendocrine signaling as a potential modulator of large-scale intra-limbic communication networks that are thought to underlie the neurophysiology of emotion.