Cindy Boer

98 | Chapter 2.2 MCP4-L MCP4-R MCP5-L MCP5-R MCP2-L MCP2-R MCP3-L MCP3-R CMC1-L CMC1-R TS-L TS-R DIP2-L DIP2-R DIP3-L DIP3-R DIP5-L DIP5-R DIP4-L DIP4-R PIP3-L PIP3-R PIP2-L PIP2-R PIP4-L PIP4-R PIP5-L PIP5-R IP-L IP-R MCP1-L MCP1-R 0 50 100 150 200 250 Euclideandistance CMC1−L DIP2−L DIP2−R DIP3−L DIP3−R DIP4−L DIP4−R IP−L IP−R MCP1−L MCP1−R MCP2−L MCP2−R MCP3−L MCP3−R MCP4−L MCP4−R MCP5−L MCP5−R PIP2−L PIP2−R PIP3−L PIP3−R PIP4−L PIP4−R PIP5−L PIP5−R TS−L TS−R Dimension1 Dimension2 Jointgroup Phenotype CMC DIP IP MCP PIP TS HandKLsum FingerKLsum ThumbKLsum DIP5−L DIP5−R CMC1−R ▲ Figure 1: Tree-dendrogram and multidimensional scaling (MDS) plot of KL scores in the joints of the hand. a. tree-dendogram of complete hierarchal clustering of Euclidean distance matrix of KL scores of groups of joints. Joints were grouped per ‘type’ and per hand, left or right. b. MDS plot of KL scores for all hand joints left (L) and right (R), not grouped per “type”. Data consisted of all available data from RSI, RSII and RSIII (n=8,691). Selected clusters are depicted by the different dashed lines. OA: osteoarthritis, KL: Kellgren-Lawrence OA severity score, TS: trapezioscaphoid joints, CMC: carpometa- carpal joints, PIP: proximal interphalangeal joints, DIP: distal interphalangeal joints, MCP: metacarpo- phalangeal joints and IP: interphalangeal joints. L/R: left or right joint, number denotes which joint, i.e., PIP2L: the second PIP joint at the left hand. See supplementary figures 2-3 for dendrogram and MDS plots for joint space narrowing and osteophytosis. (8 joints per hand, 16 joints per individual, KLsum score range: 0 - 64), and 3) Thumb KLsum=sum of KL grades across the CMC1 and TS joint (2 joints per hand, 4 joints per individual, KLsum score range: 0 - 16). Individuals with a missing KL grade in one or more hand joints were excluded from the analysis of phenotypes that required scoring of the missing joint(s). Also, individuals with missing age, sex or genetic principal com- ponents were excluded from all analyses ( Table 1 ). Post GWAS analysis Post GWAS analysis consisted of multiple bioinformatic and functional analyses ( online S upplementary T ext ). Briefly, all GWAS variants were annotated using HaploReg (V4.1) and FUMA[32, 33]. Intersection of variants with epigenetic markers, proteins, tran-scription factor (TF) motifs and binding, and chromatin interactions was done using data from ROADMAP, ENCODE, HaploReg (V4.1) and the 3D genome browser[34-37]. Functional studies included expression quantitative trait loci (eQTL) analysis, methyl-ation expression quantitative trait loci (meQTL) analysis, ATAC-seq analysis and dif-ferential gene expression analysis. All functional analyses were performed in human articular cartilage. Details are provided in the online S upplementary T ext .