Cindy Boer

168 | Chapter 4.1 Phenotype Other Phe- notypes SNV Chr:pos EA NEA EAF OR 95% CI P-value KneeOA AllOA, TJR, KneeHipOA, TKR rs143384 20:34025756 A G 0.59 1.1 1.06 - 1.09 1.01x10 -23 THR TJR rs9981408 21:40017446 T G 0.23 1.1 1.07 - 1.12 2.21x10 -12 Female specific THR rs116112221 2:59439973 T C 6.1x10 - 3 1.95 1.58 - 2.41 4.61x10 -10 THR rs10282983 8:69590554 T C 0.22 1.15 1.11 - 1.19 2.21x10 -14 AllOA rs10453201 9:34050345 T C 0.22 1.05 1.02 - 1.06 1.05x10 -08 Phenotype: Osteoarthritis phenotype with which the SNV has a genome-wide significant association (p-values 1.3x10-08).Other Phenotypes: Other osteoarthritis phenotypes that are associated with this SNV at GWS level but are less significant than OA Phenotype; AllOA, osteoarthritis (OA) at any of one or more of the investigated joint sites: hip, knee, hand, finger, thumb and spine; KneeOA OA or joint replacement at the left and/or right knee joint; HipOA, OA or joint replacement at the left and/or right hip joint; KneeHipOA, KneeOA and/or HipOA; TJR, Undergone total knee and/or hip replacement due to OA in left, right or both joints; TKR, Undergone total knee replacement due to OA in left right or both knee joints; THR, Undergone total hip replacement due to OA in left, right or both hip joints; SpineOA, Lumbar disk degeneration: narrowing, osteophytes or both present on two or more vertebral levels [REF: PMID: 20147869]; FingerOA, OA at one of the distal interphalangeal (DIP) joints 1-4, the proximial interphalangeal (PIP) joints 1-4 in the left finger and right fingers. If only data from one side (left/right) was available cases were defined on that side only. ; ThumbOA, OA at the first carpometacarpal (CMC1) joint and /or trapezioscaphoid (TS) joint in the left thumb and right thumb. If only data from one side (left/right) was available cases were defined on that side only. HandOA, FingerOA and/or ThumbOA. EA: effect allele, NEA: Non-Effect allele, EAF: effect allele frequency: aoverage frequency in the tested cohorts, OR: odds ratio. 95%CI: 95% confidence interval of the OR Female-specific osteoarthritis risk variants To investigate if the 100 SNVs confer sex-specific effects, we combined association sum- mary statistics from male-specific meta-analysis, consisting of up to 56,462 cases and 153,808 controls, and female-specific meta-analysis, consisting of up to 90,838 cases and 192,697 controls. None of the 100 SNVs showed significant differences in effect size between men and women (p-value het-diff <0.0005) ( Supplementary Table 4 ). To investi- gate the presence of any additional osteoarthritis signals specific to males only, females only, or with effects of opposite direction in men and women, we performed for each of the 11 osteoarthritis phenotypes separately, a sex-differentiated test of association and a test of heterogeneity in allelic effects[9, 10]. We identified three new female-specific independent SNVs, two of which showed significant (p-value het-diff <0.016) differences in effect size between sexes ( Supplementary Table 4 ). rs116112221 (p-value sex -dif- f=3.20x10 -09 ,p-value het-diff =4.09x10 -04 ; female OR=1.95, 95% CI= 1.58-2.41, p-value fe- male =4.61x10 -10 ; male OR=1.06, 95% CI=0.82-1.38, p-value male =0.64) is significant in the female-only total hip replacement phenotype and is located in a region containing long intergenic non coding RNAs with the closest protein coding gene being FANCL . We Table 2 (continued): Summary statistics of all Genome-Wide Significant Signals in the GO-Consortium