Cindy Boer

104 | Chapter 2.2 12 11 10 9 8 7 6 5 4 3 2 1 0 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 rs10916199 r -Log P-value 227,900,000 227,800,000 228,000,000 228,100,000 228,200,000 200 Kb ZNF678 JMJD4 ZNF847 PRSS38 WNT9A WNT3A SNAP47 human Osteoblast CTCF Chip-seq peaks RefSeq Genes SNVs (LD = r >0.8) co-localized in ATAC-seq peaks meQTL CpG sites rs10916199 rs74140304 1 Capture Hi-C human MSC human Osteoblast CTCF Chip-seq ENCODE peaks Capture Hi-C hMSC a b c d e f g 3 2 1 Chromatin state legend: ActiveTSS Enhancer Transcription Heterochromatin ZNF/repeats Quiescent Polycomb repressed weak Polycomb repressed strong cg09796739 | | cg11520395 rs11588850 human Fetal Cartilage ATAC-Seq Peaks hMSC derived Chondrogenic Cells Primary Osteoblasts Chromatin State ROADMAP primary model Proximal Tibia (E59) Proximal Femur (E59) Distal Femur (E59) Distal Tibia (E59) ▲ Figure 3: Schematic overview of part of the rs10916199 locus. a. LocusZoom plot of rs10916199 locus, the Y-axis depicts the-Log10 p-value of the SNV from the thumb KLsum GWAS. Colours depict the LD (r2) between the variant and the LD SNV rs10916199. The X-axis depicts the relative genomic loca- tion, depict are the protein coding genes at those genomic locations. For this genomic region depicted in figure b – g are several epigenetic annotations are plotted. b . Chromatin state, as predicted by the ROADMAP 15-state model on histone modifications, for primary osteoblasts and human mesenchymal stem cell derived chondrocytes. Colours depict chromatin states, legend at bottom of full figure. c. ATAC-seq peaks from human embryonic cartilage at different bone development sites at gestation day (E)59. d. Location of the lead SNV, rs10916199 and two putative causal SNV’s which co-locative with ATAC-seq peaks. e. Genomic location of rs10916199 meQTL CpG sites. f. Chip-seq CTCF protein binding peaks from human primary osteoblasts from ENCODE. g. Capture Hi-C chromatin interactions from 3D genome browser for human mesenchymal Stem Cells (hMSC) and mesoderm. Depicted are the chro- matin interactions from the promoters of the queried gene to the genomic location of interaction, this was done for the JMJD4/SNAP47 transcription start site (TSS), WNT9A TSS and the WNT3A TSS. For details on methods and underlying data see supplementary methods.