What is a good pipeline for using public domain exomes as controls? I'm currently attempting association analysis with an extremely small set of patient exomes (n=10), with no control or parental exomes available. Downloading the ExAC VCF of variant sites (http://exac.broadinstitute.org/downloads) or the 1000G integrated call sets (http://ftp.1000genomes.ebi.ac.uk/) and combining this with our pooled patient VCFs has not been successful (I suspect the approach of attempting to merge such large VCFs generated from different pipelines is rather naive).

Looking at the primary literature, I have gathered it should be possible to use these resources to help increase statistical power for our analysis. My question is how do I take these large .vcfs with many samples and successfully merge them to our patient .vcfs, such that the combined VCF can be used downstream to run analysis packages? (PODKAT, PLINK, etc.)
I gather that you want to use the background SNP frequency as a prior for input to your SNP calling algorithm?

I'm not sure of a canned algorithm for doing this, but a quick google shows up some promising links:


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3593722/
https://software.broadinstitute.org/gatk/documentation/article.php?id=4723
https://bmcbioinformatics.biomedcentral.com/articles/10.1186/s12859-015-0489-0