Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations

被引：265

作者：

Boer, Cindy G. ^{[1
]}

Hatzikotoulas, Konstantinos ^{[2
]}

Southam, Lorraine ^{[2
]}

Stefansdottir, Lilja ^{[3
]}

Zhang, Yanfei ^{[4
]}

de Almeida, Rodrigo Coutinho ^{[5
]}

Wu, Tian T. ^{[6
]}

Zheng, Jie ^{[7
]}

Hartley, April ^{[7
,8
]}

Teder-Laving, Maris ^{[9
]}

Skogholt, Anne Heidi ^{[10
]}

Terao, Chikashi ^{[11
]}

Zengini, Eleni ^{[12
]}

Alexiadis, George ^{[13
]}

Barysenka, Andrei ^{[2
]}

Bjornsdottir, Gyda ^{[3
]}

Gabrielsen, Maiken E. ^{[10
]}

Gilly, Arthur ^{[2
]}

Ingvarsson, Thorvaldur ^{[14
,15
]}

Johnsen, Marianne B. ^{[10
,16
,17
]}

Jonsson, Helgi ^{[14
,18
]}

Kloppenburg, Margreet ^{[19
,20
]}

Luetge, Almut ^{[10
]}

Lund, Sigrun H. ^{[3
]}

Magi, Reedik ^{[9
]}

Mangino, Massimo ^{[21
]}

Nelissen, Rob R. G. H. H. ^{[22
]}

Shivakumar, Manu ^{[23
]}

Steinberg, Julia ^{[2
,24
]}

Takuwa, Hiroshi ^{[25
,26
]}

Thomas, Laurent F. ^{[10
,27
,28
,29
]}

Tuerlings, Margo ^{[5
]}

Babis, George C. ^{[30
]}

Cheung, Jason Pui Yin ^{[31
]}

Kang, Jae Hee ^{[32
]}

Kraft, Peter ^{[33
]}

Lietman, Steven A. ^{[34
]}

Samartzis, Dino ^{[31
,35
]}

Slagboom, P. Eline ^{[5
]}

Stefansson, Kari ^{[3
,14
]}

Thorsteinsdottir, Unnur ^{[3
,14
]}

Tobias, Jonathan H. ^{[7
,8
]}

Uitterlinden, Andre G. ^{[1
]}

Winsvold, Bendik ^{[10
,36
,37
,38
]}

Zwart, John-Anker ^{[10
,36
,37
]}

Smith, George Davey ^{[7
,39
]}

Sham, Pak Chung ^{[40
]}

Thorleifsson, Gudmar ^{[3
]}

Gaunt, Tom R. ^{[7
]}

Morris, Andrew P. ^{[41
]}

机构：

[1] Erasmus MC, Dept Internal Med, Med Ctr, NL-3015 CN Rotterdam, Netherlands

[2] Helmholtz Zentrum Munchen, Inst Translat Genom, German Res Ctr Environm Hlth, D-85764 Neuherberg, Germany

[3] Amgen Inc, DeCODE Genet, IS-102 Reykjavik, Iceland

[4] Geisinger Hlth Syst, Genom Med Inst, Danville, PA 17822 USA

[5] Leiden Univ Med Ctr, Dept Biomed Data Sci, Sect Mol Epidemiol, Postzone S05-P, NL-2333 ZC Leiden, Netherlands

[6] Univ Hong Kong, Li Ka Shing Fac Med, Dept Psychiat, Pokfulam, Hong Kong, Peoples R China

[7] Univ Bristol, Bristol Med Sch, MRC Integrat Epidemiol Unit IEU, Oakfield House, Bristol BS8 2BN, Avon, England

[8] Univ Bristol, Musculoskeletal Res Unit, Southmead Hosp, Bristol Med Sch,Translat Hlth Sci, Oakfield House, Bristol BS10 5NB, Avon, England

[9] Univ Tartu, Estonian Genome Ctr, Inst Genom, EE-51010 Tartu, Estonia

[10] Norwegian Univ Sci & Technol, Fac Med & Hlth Sci, KG Jebsen Ctr Genet Epidemiol, Dept Publ Hlth & Nursing, N-7491 Trondheim, Norway

[11] RIKEN Ctr Integrat Med Sci, Lab Stat & Translat Genet, Yokohama, Kanagawa 2300045, Japan

[12] Dromokaiteio Psychiat Hosp, Psychiat Dept 4, Athens 12461, Greece

[13] KAT Gen Hosp, Dept Orthopaed 1, Athens 14561, Greece

[14] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland

[15] Akureyri Hosp, Dept Orthoped Surg, IS-600 Akureyri, Iceland

[16] Univ Oslo, Fac Med, Inst Clin Med, N-0316 Oslo, Norway

[17] Oslo Univ Hosp, Dept Res Innovat & Educ, Div Clin Neurosci, Res & Commun Unit Musculoskeletal Hlth FORMI, N-0424 Oslo, Norway

[18] Natl Univ Hosp Iceland, Dept Med, IS-108 Reykjavik, Iceland

[19] Leiden Univ Med Ctr, Dept Rheumatol, NL-2300 RC Leiden, Netherlands

[20] Leiden Univ Med Ctr, Dept Clin Epidemiol, NL-2300 RC Leiden, Netherlands

[21] Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England

[22] Leiden Univ Med Ctr, Dept Orthopaed, NL-2300 RC Leiden, Netherlands

[23] Univ Penn, Perelman Sch Med, Dept Biostat Epidemiol & Informat, Philadelphia, PA 19104 USA

[24] Univ Sydney, Daffodil Ctr, Sydney, NSW 1340, Australia

[25] RIKEN Ctr Integrat Med Sci, Lab Bone & Joint Dis, Tokyo 1088639, Japan

[26] Shimane Univ, Dept Orthoped Surg, Matsue, Shimane 6938501, Japan

[27] Norwegian Univ Sci & Technol, Dept Clin & Mol Med, N-7491 Trondheim, Norway

[28] Norwegian Univ Sci & Technol, BioCore Bioinformat Core Facil, N-7491 Trondheim, Norway

[29] Trondheim Reg & Univ Hosp, Clin Lab Med, St Olavs Hosp, N-7030 Trondheim, Norway

[30] Natl & Kapodistrian Univ Athens, Med Sch, Nea Ionia Gen Hosp, Dept Orthopaed 2, Athens 14233, Greece

[31] Univ Hong Kong, Dept Orthopaed & Traumatol, Pokfulam, Hong Kong, Peoples R China

[32] Brigham & Womens Hosp, Dept Med, 181 Longwood Ave, Boston, MA 02115 USA

[33] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave, Boston, MA 02115 USA

[34] Geisinger Hlth Syst, Musculoskeletal Inst, Danville, PA 17822 USA

[35] Rush Univ, Dept Orthopaed Surg, Med Ctr, Chicago, IL 60612 USA

[36] Oslo Univ Hosp, Dept Res Innovat & Educ, Div Clin Neurosci, N-0450 Oslo, Norway

[37] Univ Oslo, N-0450 Oslo, Norway

[38] Oslo Univ Hosp, Dept Neurol, N-0424 Oslo, Norway

[39] Univ Bristol, Bristol Med Sch, Populat Hlth Sci, Bristol BS8 2BN, Avon, England

[40] Univ Hong Kong, Li Ka Shing Fac Med, Pokfulam, Hong Kong, Peoples R China

[41] Univ Manchester, Ctr Genet & Genom Versus Arthrit, Ctr Musculoskeletal Res, Manchester M13 9LJ, Lancs, England

[42] Univ Nottingham, Sch Med, Fac Med & Hlth Sci, Nottingham NG5 1PB, Notts, England

[43] Univ Thessaly, Fac Med, Lab Cytogenet & Mol Genet, Larisa 41110, Greece

[44] Univ Hong Kong, Sch Biomed Sci, Pokfulam, Hong Kong, Peoples R China

[45] Norwegian Univ Sci & Technol, Fac Med & Hlth Sci, HUNT Res Ctr, Dept Publ Hlth & Nursing, N-7600 Levanger, Norway

[46] Univ Sheffield, Dept Oncol & Metab, Sheffield S10 2RX, S Yorkshire, England

[47] Univ Sheffield, Hlth Lifespan Inst, Sheffield S10 2RX, S Yorkshire, England

[48] Acad Sinica, Inst Biomed Sci, Taipei 115, Taiwan

[49] Tech Univ Munich, TUM Sch Med, D-81675 Munich, Germany

[50] Klinikum Rechts Der Isar, D-81675 Munich, Germany

来源：

CELL | 2021年 / 184卷 / 18期

基金：

英国医学研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; VITAMIN-D SUPPLEMENTATION; LUMBAR DISC DEGENERATION; LOW-BACK-PAIN; TENASCIN-C; KNEE OSTEOARTHRITIS; HUMAN IMMUNODEFICIENCY; CARTILAGE VOLUME; POINT MUTATIONS; QUALITY-CONTROL;

D O I：

10.1016/j.cell.2021.07.038

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Osteoarthritis affects over 300 million people worldwide. Here, we conduct a genome-wide association study meta-analysis across 826,690 individuals (177,517 with osteoarthritis) and identify 100 independently associated risk variants across 11 osteoarthritis phenotypes, 52 of which have not been associated with the disease before. We report thumb and spine osteoarthritis risk variants and identify differences in genetic effects between weight-bearing and non-weight-bearing joints. We identify sex-specific and early age-at-onset osteoarthritis risk loci. We integrate functional genomics data from primary patient tissues (including articular cartilage, subchondral bone, and osteophytic cartilage) and identify high-confidence effector genes. We provide evidence for genetic correlation with phenotypes related to pain, the main disease symptom, and identify likely causal genes linked to neuronal processes. Our results provide insights into key molecular players in disease processes and highlight attractive drug targets to accelerate translation.

引用

页码：4784 / +

页数：52

共 223 条

[21] Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis [J].

Castano-Betancourt, Martha C. ;

Evans, Dan S. ;

Ramos, Yolande F. M. ;

Boer, Cindy G. ;

Metrustry, Sarah ;

Liu, Youfang ;

den Hollander, Wouter ;

van Rooij, Jeroen ;

Kraus, Virginia B. ;

Yau, Michelle S. ;

Mitchell, Braxton D. ;

Muir, Kenneth ;

Hofman, Albert ;

Doherty, Michael ;

Doherty, Sally ;

Zhang, Weiya ;

Kraaij, Robert ;

Rivadeneira, Fernando ;

Barrett-Connor, Elizabeth ;

Maciewicz, Rose A. ;

Arden, Nigel ;

Nelissen, Rob G. H. H. ;

Kloppenburg, Margreet ;

Jordan, Joanne M. ;

Nevitt, Michael C. ;

Slagboom, Eline P. ;

Hart, Deborah J. ;

Lafeber, Floris ;

Styrkarsdottir, Unnur ;

Zeggini, Eleftheria ;

Evangelou, Evangelos ;

Spector, Tim D. ;

Uitterlinden, Andre G. ;

Lane, Nancy E. ;

Meulenbelt, Ingrid ;

Valdes, Ana M. ;

van Meurs, Joyce B. J. .

PLOS GENETICS, 2016, 12 (10)

[22] Prevalence and Pattern of Lumbar Magnetic Resonance Imaging Changes in a Population Study of One Thousand Forty-Three Individuals [J].

Cheung, Kenneth M. C. ;

Karppinen, Jaro ;

Chan, Danny ;

Ho, Daniel W. H. ;

Song, You-Qiang ;

Sham, Pak ;

Cheah, Kathryn S. E. ;

Leong, John C. Y. ;

Luk, Keith D. K. .

SPINE, 2009, 34 (09) :934-940

[23] Tutorial: a guide to performing polygenic risk score analyses [J].

Choi, Shing Wan ;

Mak, Timothy Shin-Heng ;

O'Reilly, Paul F. .

NATURE PROTOCOLS, 2020, 15 (09) :2759-2772

[24] PRSice-2: Polygenic Risk Score software for biobank-scale data [J].

Choi, Shing Wan ;

O'Reilly, Paul F. .

GIGASCIENCE, 2019, 8 (07)

[25] Direct assessment of articular cartilage and underlying subchondral bone reveal's a progressive gene expression change in human osteoarthritic knees [J].

Chou, C. -H. ;

Lee, C. -H. ;

Lu, L. -S. ;

Song, I-W. ;

Chuang, H. -P. ;

Kuo, S. -Y. ;

Wu, J. -Y. ;

Chen, Y. -T. ;

Kraus, V. B. ;

Wu, C. -C. ;

Lee, M. T. M. .

OSTEOARTHRITIS AND CARTILAGE, 2013, 21 (03) :450-461

[26] Genome-wide expression profiles of subchondral bone in osteoarthritis [J].

Chou, Ching-Heng ;

Wu, Chia-Chun ;

Song, I-Wen ;

Chuang, Hui-Ping ;

Lu, Liang-Suei ;

Chang, Jen-Huei ;

Kuo, San-Yuan ;

Lee, Chian-Her ;

Wu, Jer-Yuarn ;

Chen, Yuan-Tsong ;

Kraus, Virginia Byers ;

Lee, Ming Ta Michael .

ARTHRITIS RESEARCH & THERAPY, 2013, 15 (06)

[27] Disease-Modifying Effects of a Novel Cathepsin K Inhibitor in Osteoarthritis A Randomized Controlled Trial [J].

Conaghan, Philip G. ;

Bowes, Michael A. ;

Kingsbury, Sarah R. ;

Brett, Alan ;

Guillard, Gwenael ;

Rizoska, Biljana ;

Sjogren, Niclas ;

Graham, Philippa ;

Jansson, Asa ;

Wadell, Cecilia ;

Bethell, Richard ;

Ohd, John .

ANNALS OF INTERNAL MEDICINE, 2020, 172 (02) :86-+

[28] Agammaglobulinemia and absent B lineage cells in a patient lacking the p85α subunit of PI3K [J].

Conley, Mary Ellen ;

Dobbs, A. Kerry ;

Quintana, Anita M. ;

Bosompem, Amma ;

Wang, Yong-Dong ;

Coustan-Smith, Elaine ;

Smith, Amber M. ;

Perez, Elena E. ;

Murray, Peter J. .

JOURNAL OF EXPERIMENTAL MEDICINE, 2012, 209 (03) :463-470

[29] Cux1 and Cux2 Regulate Dendritic Branching, Spine Morphology, and Synapses of the Upper Layer Neurons of the Cortex [J].

Cubelos, Beatriz ;

Sebastian-Serrano, Alvaro ;

Beccari, Leonardo ;

Elisa Calcagnotto, Maria ;

Cisneros, Elsa ;

Kim, Seonhee ;

Dopazo, Ana ;

Alvarez-Dolado, Manuel ;

Miguel Redondo, Juan ;

Bovolenta, Paola ;

Walsh, Christopher A. ;

Nieto, Marta .

NEURON, 2010, 66 (04) :523-535

[30] Next-generation genotype imputation service and methods [J].

Das, Sayantan ;

Forer, Lukas ;

Schoenherr, Sebastian ;

Sidore, Carlo ;

Locke, Adam E. ;

Kwong, Alan ;

Vrieze, Scott I. ;

Chew, Emily Y. ;

Levy, Shawn ;

McGue, Matt ;

Schlessinger, David ;

Stambolian, Dwight ;

Loh, Po-Ru ;

Iacono, William G. ;

Swaroop, Anand ;

Scott, Laura J. ;

Cucca, Francesco ;

Kronenberg, Florian ;

Boehnke, Michael ;

Abecasis, Goncalo R. ;

Fuchsberger, Christian .

NATURE GENETICS, 2016, 48 (10) :1284-1287

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