This is a duplicate of:

 1. https://www.biostars.org/p/7372/ from 5.4 years ago and
 2. https://www.biostars.org/p/65920/ from 3.5 years ago.

Nevertheless, I found the answers on the second post enlightening, and 3.5 years later it seems worthwhile to have an update from the community (and @lh3) on how you deal with these issues.

Notably, @Aaronquinlan's gemini from the second most upvoted answer to question #2 is still under active development. Are people using it? What else are people doing?
This is called "variant warehousing" and there are several open source and commercial efforts in various stages:

    Golden Helix VSWarehouse
    Paradigm4 SciDB
    WuXi NextCODE
    CMH Variant Warehouse
    ViaGenetics Genesis
    Curoverse Lightning
    Intel GenomicsDB
    Cloudera OMICS

