For that reason I think that placing most of the buttons and the quick slots on the bottom of the U will be a better idea (portraits on the left or right vertical bar will mostly be used for monitoring). I believe that in most cases (especially if one like to center its party on screen during combat) mouse travel from character-model to bottom-center will be shorter and additionally I find a horizontal buttons-bar to be more comfortable to use.
Certainly bottom center for buttons is most convenient. Unfortunately, Josh Sawyer stated that they don't want excessive mouse travel from portraits to buttons.
I don't know the exact game mechanisms but, for example, in DA the buttons are on a horizontal bar and the portraits are placed vertically. I find the DA UI during combat/exploration to be convenient and I don't remember any excessive mouse travel (on my 24" display). Another point to consider is that horizontal buttons bar enable placing a lot of quick slots that will enable direct acces and so reducing the need for pop-up menus. Maybe having mini portrait(s) on the horizontal bar in addition to large portraits on a vertical bar will make every one happy? Another option is to have compact UI (i.e. few buttons that open pop-up menus) near the vertical portraits in addition to fully or semi customize bottom-center buttons bar.
I don't uderstand why sub-menus that are opened from bottom-center are more problematic then those that are opened from the right bar. Additionally, without knowing the exact game mechanisms and taking DA as an example, the bottom-center can be width enough to eliminate the need of sub-menus.