General questions about interpretation of differential peaks

[Pirhhot]

Hello,

I am working on a project necessitating paired differential analysis between conditions.
As such, I am doing the pipeline of differential accessible regions accross my samples and integrating the results afterwards.

Unfortunately, my results are very variable in ways that I would not have thought beforehand.
As such, I wanted to check if this variability could be understood from a technical standpoint in terms of threshold selection or number of cells per group for instance.

Firstly, the differential accessible peaks' volcalno plots seem to show very skewed results towards one condition rather than having a balanced number of significant peaks enriched in each condition.
Sometimes in one way :

Sometimes in the other :

I would interpret it as a global higher openness of the chromatin in the condition with the highest number of differential peaks but I would want to be sure that this behaviour is not simply due to a mistake in selecting the right preprocessing parameters.

Furthermore, I also have a high variability in the number of significant differential peaks :
Sometimes there are very few :

Sometimes there are A LOT (here more than 30 % of the peaks)

I am going to look into the quality parameters of the cells used for differential analysis and test different parameters for Group Coverages. But I would love to hear if anyone has run into similar issues and could recommend critical parameters to look into, or best practices for ensuring robust and interpretable differential analysis.

Thank you very much in advance for your help.