Cindy Boer

70 | Chapter 2.1 ▲ Figure 1: Manhattan plot for association of mJSW in the discovery phase . The-log 10 p-values, for each of the 2.5 million tests performed as part of the genome wide association of minimal joint space width of the hip (mJSW), plotted against their position per chromosome. Full results of the discovery GWAS are accessible through https://www.glimdna.org. The grey solid horizontal line corresponds to the genome-wide significant threshold (p-value=5x10 -08 ). The dotted grey line corresponds to the selec- tion for replication threshold (p-value=1x10 -05 ). approaches that leverage different levels of information to enforce evidence of candi- date genes annotated close to the associated signals. Results Identification of novel genetic loci associated with cartilage thickness Genome-wide Association analysis of mJSW of the hip with genetic variants was per- formed in a discovery set that included 13,013 individuals (see Supplementary Table 1 and Supplementary Text 1 for cohort specifics) with data on ±2,5 million genotyped or HapMap Phase II imputed SNPs. We applied extensive quality control measures (see Supplementary Table 2 and Supplementary Table 3 for details on quality control and exclusion criteria) leaving a total of 2,385,183 SNPs available for association analyses. Genomic control inflation factors for the p-values of the RS, TwinsUK, MrOS, and SOF GWAS were low (λ=1.02, 1.01, 1.02 and 0.99 respectively), and the inter quantile-quan- tile plot ( Supplementary Figure 1 ) also indicated no residual population stratification due to cryptic relatedness, population substructure or other biases. The discovery analysis yielded eighteen independent SNPs with suggestive evi- dence for association (p-value<1x10 −05 ) with mJSW, of which five (four genetic loci) met the genome-wide significance threshold of p-value≤5*10 −08 ( Figure 1 ). The top SNPs