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Genetics of Osteoarthritis 66 2 67 3 a a * 68 Q7 G YJOCA4821_proof ■ 24 March 2021 ■ 1/15 Osteoarthritis and Cartilage xxx (xxxx) xxx 55 56 57 58 59 60 61 62 63 Review 64 65 1 Q8 Genetics of osteoarthritis 66 2 67 3 a a * 68 Q7 G. Aubourg , S.J. Rice , P. Bruce-Wootton, J. Loughlin 4 69 5 Biosciences Institute, Newcastle University, Newcastle Upon Tyne, UK 70 6 71 7 72 8 article info summary 73 9 74 10 Article history: Osteoarthritis genetics has been transformed in the past decade through the application of large-scale 75 Received 11 December 2020 11 genome-wide association scans. So far, over 100 polymorphic DNA variants have been associated with 76 Accepted 6 March 2021 this common and complex disease. These genetic risk variants account for over 20% of osteoarthritis 12 77 13 heritability and the vast majority map to non-protein coding regions of the genome where they are Keywords: fi 78 14 presumed to act by regulating the expression of target genes. Statistical ne mapping, in silico analyses of Genetics genomics data, and laboratory-based functional studies have enabled the identification of some of these 79 15 Epigenetics targets, which encode proteins with diverse roles, including extracellular signaling molecules, intracel- 80 SNPs 16 lular enzymes, transcription factors, and cytoskeletal proteins. A large number of the risk variants 81 17 GWAS DNA methylation correlate with epigenetic factors, in particular cartilage DNA methylation changes in cis, implying that 82 18 Functional analysis epigenetics may be a conduit through which genetic effects on gene expression are mediated. Some of 83 19 the variants also appear to have been selected as humans adapted to bipedalism, suggesting that a 84 20 proportion of osteoarthritis genetic susceptibility results from antagonistic pleiotropy, with risk variants 85 21 having a positive role in joint formation but a negative role in the long-term health of the joint. Although 86 data from an osteoarthritis genetic study has not yet directly led to a novel treatment, some of the 22 87 osteoarthritis associated genes code for proteins that have available therapeutics. Genetic investigations 23 88 24 are therefore revealing fascinating fundamental insights into osteoarthritis and can expose options for translational intervention. 89 25 © 2021 The Author(s). Published by Elsevier Ltd on behalf of Osteoarthritis Research Society 90 26 International. This is an open access article under the CC BY license (http://creativecommons.org/ 91 27 licenses/by/4.0/). 92 28 93 29 94 30 95 31 96 32 Q1 Introduction Osteoarthritis (OA) has been subjected to such detailed genetic 97 33 investigation and each year new OA susceptibility risk loci are re- 98 34 Comprehensive molecular genetic investigations into multifac- ported, along with subsequent mechanistic investigations that help 99 35 torial human diseases have been a scientific highlight of the past to clarify how genetic risk impacts the cells and tissues of the 100 36 decade. Such analyses have garnered insights into fundamental articulating joint. In this review we summarize the current status of 101 37 aspects of disease pathophysiology, identifying gene targets and OA genetics, from discovery of risk loci and their functional inves- 102 38 biological pathways for therapeutic intervention. These genetic tigation, through to epigenetics and the clinical utility of the new 103 39 studies involve the genome-wide association scan (GWAS) of DNA knowledge. 104 40 variants, principally mapping alleles at single nucleotide poly- 105 41 morphisms (SNPs), in cases and controls. The use of large cohorts, 106 OA is a polygenic disease 42 often involving hundreds of thousands of individuals, and high- 107 43 density SNP genotyping arrays supplemented by statistical impu- 108 Investigators conducting OA GWAS have focused on cases 44 tation has enabled tens of thousands of DNA variants to be asso- 109 1 diagnosed with the typical age-related form of the disease, in which 45 ciated with a broad range of diseases . 110 onset occurs from the fifth decade of life. Furthermore, individuals 46 111 with post-traumatic OA, or another obviously non-genetic cause of 47 112 disease, are often excluded from analyses. The logic here is that the 48 113 * Address correspondence and reprint requests to: J. Loughlin, Newcastle Uni- case group will then consist of individuals who are more likely to 49 versity, Biosciences Institute, International Centre for Life, Newcastle upon Tyne, 114 have a genetic component underlying their disease. This is the most 50 NE1 3BZ, United Kingdom. Tel.: 44 (0)191-241-8988; Fax: 44 (0)191-241-8666. 115 common form of OA, which consequently confers the highest 51 E-mail address: [email protected] (J. Loughlin). 116 a These authors contributed equally. burden upon society. Selection of OA cases has involved a range of 52 117 53 https://doi.org/10.1016/j.joca.2021.03.002 118 54 1063-4584/© 2021 The Author(s). Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International. This is an open access article under the CC BY license 119 (http://creativecommons.org/licenses/by/4.0/). Please cite this article as: Aubourg G et al., Genetics of osteoarthritis, Osteoarthritis and Cartilage, https://doi.org/10.1016/j.joca.2021.03.002 YJOCA4821_proof ■ 24 March 2021 ■ 2/15 2 G. Aubourg et al. / Osteoarthritis and Cartilage xxx (xxxx) xxx 1 66 2 67 3 68 4 69 Chromosome Association SNP Nearerst protein coding gene EA/NEA OR Variant (chromatin state) Position (hg19) P-value Causal gene Reference 5 70 À 1 rs3753841 COL11A1 A/G 1.08 Missense (Transcribed) 10,33,79,918 5.20 Â 10 10 22 6 À 71 rs2126643 COL11A1 C/T 1.10 Intronic (Transcribed) 10,34,04,384 2.10 Â 10 14 22 7 rs4338381 COL11A1 A/G 1.10 Intronic (Promoter) 10,35,72,927 4.37 Â 10À15 24 72 À 8 chr1:150214028 ANP32E C/CT 1.03 Intergenic 15,02,14,028 2.54 Â 10 8 24 73 À 9 rs550034492 RABGAP1L TA(17)/T 1.03 Intronic (Transcribed) 17,41,92,403 1.05 Â 10 8 24 74 À rs11583641 COLGALT2 C/T 1.08 30UTR (Transcribed) 18,39,06,245 5.58 Â 10 10 COLGALT2 24 10 À 75 rs2820436 ZC3H11B A/C 1.07 Intergenic (Enhancer) 21,96,40,680 2.01 Â 10 9 21 11 À 76 rs2785988 SLC30A10 A/C 1.08 Intergenic (Repressed) 21,97,44,138 3.90 Â 10 10 22 À 12 rs2820443 SLC30A10 C/T 1.06 Intergenic (Enhancer) 21,97,53,509 2.01 Â 10 9 21 77 À 13 1.06 6.01 Â 10 11 24 78 À 14 rs10916199 ZNF678 A/G ns Intronic (Heterochromatin) 22,79,02,472 2.4 Â 10 13 WNT9A 25 79 À rs10218792 KIF26B G/T 1.04 Intronic (Transcribed) 24,57,50,932 2.03 Â 10 8 24 15 À 80 2 rs2061027 LTBP1 A/G 1.04 Intronic (Transcribed) 33,43,336 3.16 Â 10 13 24 À 16 rs2061026 LTBP1 A/G 1.06 Intronic (Enhancer) 33,43,549 1.40 Â 10 11 22 81 À 17 rs2862851 TGFA C/T ns Intronic (Repressed) 7,07,12,802 5.20 Â 10 11 14 82 À 18 rs3771501 TGFA A/G 1.06 Intronic (Repressed) 7,07,17,653 1.66 Â 10 8 21 83 À 1.05 4.24 Â 10 16 24 19 À 84 rs12470967 SDPR A/G 1.06 Intergenic 19,26,71,981 1.50 Â 10 8 24 20 À 85 rs62182810 RAPH1 A/G 1.03 Intronic (Transcribed) 20,43,87,482 1.65 Â 10 9 24 À 21 3 rs7639618 COL6A4P1 G/A 1.43 Missense (Repressed) 1,52,16,429 7.3 Â 10 11 3 86 À 22 rs62262139 RBM6 A/G 1.04 Intronic (Transcribed) 5,00,22,049 9.09 Â 10 11 24 87 À 23 rs11177 GNL3 A/G 1.12 Missense (Transcribed) 5,27,21,305 1.25 Â 10 10 8 88 À rs6976 GNL3 T/C 1.12 30UTR (Transcribed) 5,27,28,804 7.24 Â 10 11 8 24 À 89 rs3774355 ITIH1 A/G 1.09 Intronic (Repressed) 5,28,17,778 8.20 Â 10 14 24 À 25 rs678 ITIH1 T/A 1.08 Missense (Repressed) 5,28,20,981 1.60 Â 10 9 22 90 26 rs12107036 TP63 G/A 1.21 Intronic 18,96,00,160 2.15 Â 10À3 8 91 À 27 4 rs11732213 SLBP T/C 1.06 Intronic (Transcribed) 17,04,244 8.81 Â 10 10 24 92 À rs1913707 RAB28 A/G 1.08 Intergenic 1,30,39,440 2.96 Â 10 11 24 28 À 93 rs34811474 ANAPC4 G/A 1.04 Intronic (Transcribed) 2,54,08,838 2.17 Â 10 9 24 29 À 94 rs11335718 ANXA3 -/C 1.11 Intronic (Transcribed) 7,95,28,543 4.26 Â 10 8 21 À 30 rs13107325 SLC39A8 T/C 1.10 Missense (Transcribed) 10,31,88,709 8.29 Â 10 19 24 95 À 31 5 rs10471753 PIK3R1 G/C ns Intergenic (Enhancer) 6,78,18,952 3.80 Â 10 9 14 96 À 32 rs35611929 AP3B1 A/G 1.06 Intronic (Transcribed) 7,74,67,824 8.29 Â 10 19 24 97 À rs3884606 FGF18 G/A 1.04 Intronic (Enhancer) 17,08,71,074 8.25 Â 10 9 24 33 À 98 6 rs1800562 HFE G/A 1.95 Missense (Transcribed) 2,60,93,141 5.0 Â 10 14 22 34 À 99 rs115740542 HIST1H2BC C/T 1.06 Intergenic (Promoter) 2,61,23,502 8.59 Â 10 9 24 À 35 rs10947262 BTNL2 C/T 1.31 Intronic (Repressed) 3,23,73,312 5.0 Â 10 9 4 100 À 36 rs7775228 HLA-DQB1 T/C 1.34 Intergenic (Repressed) 3,26,58,079 2.43 Â 10 8 4 101 À rs9277552 HLA-DPB1 C/T 1.06 30UTR (Transcribed) 3,30,55,501 2.37 Â 10 10 24 37 À 102 rs12154055 CDC5L G/A 1.03 Intergenic 4,44,49,697 2.71 Â 10 8 24 38 À 103 rs10948155 SUPT3H/RUNX2 C/T ns Intergenic 4,46,87,987 5.20 Â 10 11 RUNX2 14 À 39 rs10948172 SUPT3H/RUNX2 G/A 1.14 Intronic (Enhancer) 4,47,77,961 7.92 Â 10 8 RUNX2 8 104 À 40 9.00 Â 10 11 22 105 À 41 rs2396502 SUPT3H/RUNX2 C/A 1.09 Intronic (Transcribed) 4,53,57,699 2.12 Â 10 12 24 106 À rs1997995 SUPT3H/RUNX2 G/A 1.09 Intronic (Transcribed) 4,53,74,183 1.1 Â 10 11 22 42 À 107 rs12206662 SUPT3H/RUNX2 G/A ns Intronic (Transcribed) 4,53,76,221 1.3 Â 10 9 14 43 À 108 rs80287694 BMP5 G/A 1.12 Intronic 5,56,36,940 2.66 Â 10 9 24 À 44 rs12209223 FILIP1 A/C 1.16 Intronic 7,61,64,589 2.9 Â 10 15 22 109 À 45 1.17 3.88 Â 10 16 24 110 À rs9350591 FILIP1 T/C 1.18 Intergenic 7,62,41,527 2.42 Â 10 9 8 46 À 111 7 rs143083812 SMO T/C 2.84 Missense (Transcribed) 1,28,84,410 7.90 Â 10 12 22 47 À 112 rs11764536 HDAC9 C/A 1.26 Intronic 1,84,09,993 1.60 Â 10 9 22 À 48 rs788748 IGFBP3 A/G
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