Fig. 5: Parathyroid-associated GWAS SNPs are enriched in regulatory regions in parathyroids.

a Enrichment of GWAS SNPs for PTH level, bone density and osteoporosis, in regulatory elements of parathyroids. p-values by a one-sided Fisher’s exact test. The sizes of circles correspond to odds ratios and colors to p-values. The regulatory elements include all promoters and enhancers in parathyroids. b PTH level-associated SNP (rs9811123) in the parathyroid-specific intronic enhancer of CASR. Profiles of GCM2 ChIP-seq, DNase-seq, chromatin states, and DHSs in parathyroids. The colors represent each chromatin state. Y-axis: normalized read densities for GCM2 ChIP-seq, and DNase-seq. The scale of the value is indicated in parentheses. The PTH SNP overlaps with GCM2 peak, parathyroid-specific DHS and super-enhancer. c Read depths at the PTH-level SNP rs9811123 from one of the heterozygote GCM2 ChIP-seq samples from this study showing 59 reads (67%, orange) mapping to the reference sequence while 29 (33%, green) reads mapping to the alternative sequence. d Motif sequence of HINFP around rs9811123, for which the binding affinity change by the SNP was predicted. e Effect of the SNP measured by luciferase assays in HEK293 and in DF-1. n = 4 biologically independent samples; 3 repeated measurements for each biological sample. Rep, biological replicate. Distinct dot shapes correspond to distinct samples. p-values obtained through one-sided Student’s t-tests on 4 biological replicates. The mean of 3 repeated measurements was used for each biological replicate. The bar graph displays the mean values of biological replicates with error bars of ±SEM (standard error of the mean). f Chromatin states around RALB gene in parathyroid (this study) and other tissues profiled in Roadmap Epigenomics. The same colors for chromatin states as in panel b, e.g., red and yellow colors indicating active promoter state and enhancer state, respectively. Arrows indicate transcription starting site and transcription direction. g Expression levels of RALB across tissue types. Orange: parathyroid, Gray: other tissue types from the GTEx project. n = 8, biologically independent samples for parathyroids. The box represents the interquartile range (IQR) divided by the median, and Tukey whiskers extend to a maximum of 1.5 × IQR beyond the box. h PTH level-associated SNP (rs6542579) in the parathyroid-specific intronic enhancer of RALB. Profiles of GCM2 ChIP-seq, DNase-seq, chromatin states, and DHSs. Y-axis: normalized read densities for GCM2 ChIP-seq and DNase-seq. The scale of the value is indicated in parentheses. The PTH-level SNP overlaps the GCM2 peak, parathyroid specific DHS and super-enhancer.