You won't do it by layers, if they have all been merged "flat" to save the picture. Often, a give away is just visual, where the artiste has overlooked something, such as a single shadow maybe. However, if you really blow it up, you might find discrepancies in outlines, where a selection has missed a few pixels etc.
The easiest check is to see if there is any EXIF information with the shot. If there is, then you are almost certainly looking at the real thing.
Conan