Fables is probably one of the best comic series ever written, although you would have to jump back a bit and read the trades to truly make sense of it. There was one crossover but it was only for three issues and was easy to follow. Fables had/has a few spin off books that are all quite good and enrich the universe, but aren't typically required (Jack of Fables, Fairest, Cinderella, the Literals).
Most vertigo books are pretty self contained. American Vampire is always excellent.
In regards to DC, I find that Batwoman to be one of the strongest titles and really is a standalone title. While it may reference other events, it doesn't crossover with other books.
Locke and Key, while drawing to an end, is a fantastic book that is straightforward and tells a great story.
I've also been enjoying exploring the more independant side of graphic novels through books by the likes of Derf Backderf, Chester Brown, Charles Burns, and Brosgol.