Cross-linking pathological and clinical observations in depression and anxiety: building a genetic bridge

Tineke van Veen – Dept. of Psychiatry, Leiden University Medical Centre, The Netherlands

We previously found different gene sets to contribute to different symptom dimensions of depression and anxiety. We hypothesised that different gene sets are associated with different neuropathological characteristics, which in turn lead to different clinical phenotypes.

We used data from the Stanley Neuropathology Consortium Integrative Database. From the genome-wide genotype data (n=56), we extracted the 11 gene sets previously associated with General Distress, Anhedonic Depression, and Anxious Arousal. From the 1794 neuropathological measures, we selected 77 mainly structural parameters in the hippocampus, prefrontal cortex and amygdala. Using the Globaltest, we analysed associations between the 11 gene sets and the 77 neuropathological phenotypes. Where necessary, we adjusted for age, gender, disease duration, post-mortem interval, brain pH, fixation time, or antipsychotic medication.

We observed several associations of gene sets with neuropathological outcome measures. For instance, the pathway “Epigenetic changes after fear conditioning” was associated with Anhedonic Depression in living patients with a major depressive disorder (MDD). In brain donors, this pathway was associated with size of pyramidal neurons in prefrontal cortex (PFC), and with synaptic densities in hippocampus (SNAP25, synapsin and complexin 2). Pathway “Dorso-ventral axis formation” was associated with Anxious Arousal in patients with MDD. In brain donors, it was associated with GAD67 expression in the basolateral nucleus of the amygdala.

With these observations, we provide proof of principle of the approach to link genetic risk, neuropathological features and symptoms into a more integral view on depression and anxiety.

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