Disease. I just read 1491 so I'm pretty much an expert
That's a pretty good book. It was just about 100% disease, but I really don't think any organized, centralized government lets a bunch of foreigners who clearly have superior technology just create settlements on their land. Without the settlements and trade, I really don't think the disease would have been as much of a factor.
If the natives of the Bahamas just would have killed Columbus and burned his ships, the world would look a whole lot different today.