Disease-associated SNPs are enriched within PPSs in human transcripts. (A) Enrichment of disease-associated SNPs from dbSNP build 137 and the NHGRI GWAS Catalog in PPSs versus background. *** denotes P → 0 and ** denotes P < 0.001 (chi-squared test). (B) Ratio of synonymous to non-synonymous SNPs in PPSs versus background. ** denotes P < 0.001 (chi-squared test). (C,D) Two examples of disease-related SNPs found in UROD (C) and PARK7 (D) that overlap with PPSs identified by PIP-seq in HeLa cells using ssRNase treatment (SSase). The screenshots are from our PIP-seq browser . The UROD and PARK7 SNPs (as indicated in the flagged SNPs track) are used in the analyses shown in (E) and (F), respectively. A blue line below the transcript model denotes the regions used for the analyses in (E) and (F). (E,F) UV-cross-linking analysis of normal compared to disease-related SNPs using probes with only the specific base pair substitution, as specified in parentheses next to the disease label, and protein lysates from HeLa cells. The rs121918066 (E) and rs74315352 (F) SNPs associated with porphyria cutanea tarda and early-onset Parkinson’s disease, respectively, were used in this analysis. Representative images for three replicate experiments. ** denotes P < 0.001 (one-tailed t-test). bkgd, background; PIP-seq, protein interaction profile sequencing; PPS, protein-protected site; SNP, single nucleotide polymorphism; SSase, ssRNase treatment.