As a new player, I can tell you what the first change to the default game settings I made was: I turned off music while riding. I played around with the UI a bit, later, but the next major change was fixing the raid info boxes, which by default are smack in the middle of your screen, right where, you know, you're fighting things.
So...anyone remember the first things you changed once you realized you could? Or, alternately, since the game saves UI settings locally, the first changes you make when you get a new computer, or just play on a different one?