Nickerson's work focused on the application of genomic technologies to understand genetic variation underlying human health and disease, and advanced the idea of cataloging human genomic diversity to improve genetic discoveries and diagnoses.
Notable work by Nickerson's group included illuminating of the pharmacogenomics of warfarin dosing, and producing early catalogs of normal human genomic variation. Using exome sequencing, Nickerson also identified the gene for Miller syndrome with her colleagues Michael Bamshad and Jay Shendure. The study was the first to illustrate the practicality of using genomic technologies to identify the genes underlying rare Mendelian disorders by studying a small number of unrelated affected individuals.