One explanation is that Berlin is not a hub. Another reason is that the airports in Berlin are relatively small. The DDR past also likely has to something to do with it. Frankfurt is somewhat central and convenient. While Frankfurt's population may not be that high in comparison to other cities, there's a large population in the surrounding area.

Munich is also a big airport--not quite as much volume as FRA, but pretty close.

Berlin does have flights to the US--EWR and JFK come to mind.