Since the sequencing of the first human genome in 2001, more than 3000 human genomes have been sequenced and more than 150 million SNPs have been identified in those genomes. Many of the SNPs lie in regions of genes that encode proteins and potentially impact function and contribute to disease. However, the vast majority of SNPs lie outside protein-coding regions and hence their impact on human physiology and disease, if any, is much more ambiguous. We developed a high throughput assay using Protein Binding Microarrays (PBMs) to identify SNPs that alter the ability of transcription factors to bind DNA. We used human ChIPseq data and Quantitative Trait Loci (eQTLs) from the Genotype Tissue Expression (GTEx) project supported by the NIH Common Fund to identify >15,000 affinity altering SNPs (aaSNPs) for 9 nuclear receptors, the majority of which correlate with gene expression in human tissue. We will discuss some of the challenges of the project from the standpoint of data and genome science as well as the potential implications for precision medicine.