Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis

被引：75

作者：

Castano-Betancourt, Martha C. ^{[1
]}

Evans, Dan S. ^{[2
]}

Ramos, Yolande F. M. ^{[3
]}

Boer, Cindy G. ^{[1
]}

Metrustry, Sarah ^{[4
]}

Liu, Youfang ^{[5
]}

den Hollander, Wouter ^{[3
]}

van Rooij, Jeroen ^{[1
]}

Kraus, Virginia B. ^{[6
,7
]}

Yau, Michelle S. ^{[8
,9
]}

Mitchell, Braxton D. ^{[8
,9
,10
]}

Muir, Kenneth ^{[11
]}

Hofman, Albert ^{[12
,13
]}

Doherty, Michael ^{[14
]}

Doherty, Sally ^{[14
]}

Zhang, Weiya ^{[14
]}

Kraaij, Robert ^{[1
]}

Rivadeneira, Fernando ^{[1
]}

Barrett-Connor, Elizabeth ^{[15
]}

Maciewicz, Rose A. ^{[16
]}

Arden, Nigel ^{[17
]}

Nelissen, Rob G. H. H. ^{[18
]}

Kloppenburg, Margreet ^{[19
,20
]}

Jordan, Joanne M. ^{[5
]}

Nevitt, Michael C. ^{[21
]}

Slagboom, Eline P. ^{[3
]}

Hart, Deborah J. ^{[4
]}

Lafeber, Floris ^{[22
]}

Styrkarsdottir, Unnur ^{[23
]}

Zeggini, Eleftheria ^{[24
]}

Evangelou, Evangelos ^{[25
,26
]}

Spector, Tim D. ^{[4
]}

Uitterlinden, Andre G. ^{[1
,12
]}

Lane, Nancy E. ^{[21
,27
]}

Meulenbelt, Ingrid ^{[3
]}

Valdes, Ana M. ^{[14
]}

van Meurs, Joyce B. J. ^{[1
]}

机构：

[1] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands

[2] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA

[3] Leiden Univ, Med Ctr, Sect Mol Epidemiol, Dept Med Stat & Bioinformat, Leiden, Netherlands

[4] Kings Coll London, Dept Twins Res & Genet Epidemiol Unit, London, England

[5] Univ N Carolina, Thurston Arthrit Res Ctr, Chapel Hill, NC USA

[6] Duke Univ, Sch Med, Duke Mol Physiol Inst, Durham, NC USA

[7] Duke Univ, Sch Med, Div Rheumatol, Durham, NC USA

[8] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA

[9] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA

[10] Baltimore Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD USA

[11] Univ Warwick, Hlth Sci Res Inst, Warwick, England

[12] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands

[13] Harvard TH Sch Publ Hlth, Dept Epidemiol, Boston, MA USA

[14] Univ Nottingham, Sch Med, Nottingham, England

[15] Univ Calif San Diego, Div Epidemiol, Family Med & Publ Hlth Dept, La Jolla, CA 92093 USA

[16] AstraZeneca AB, Resp Inflammat Autoimmun Innovat Med, Molndal, Sweden

[17] Univ Oxford, Nuffield Dept Orthopaed Rheumatol & Musculoskelet, Oxford OX1 2JD, England

[18] Leiden Univ, Med Ctr, Dept Orthopaed, Leiden, Netherlands

[19] Leiden Univ, Med Ctr, Dept Rheumatol, Leiden, Netherlands

[20] Leiden Univ, Med Ctr, Dept Clin Epidemiol, Leiden, Netherlands

[21] Univ Calif San Francisco, San Francisco, CA 94143 USA

[22] Univ Med Ctr Utrecht, Utrecht, Netherlands

[23] Decode Genet, Reykjavik, Iceland

[24] Wellcome Trust Sanger Inst, Hinxton, England

[25] Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, Ioannina, Greece

[26] Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England

[27] Univ Calif Davis, Sch Med, Sacramento, CA 95817 USA

来源：

PLOS GENETICS | 2016年 / 12卷 / 10期

基金：

美国国家卫生研究院; 英国惠康基金;

关键词：

GENOME-WIDE ASSOCIATION; TRANSFORMING-GROWTH-FACTOR; SUSCEPTIBILITY LOCI; BONE; METAANALYSIS; IDENTIFY; IDENTIFICATION; ARCHITECTURE; INSIGHTS; BROWSER;

D O I：

10.1371/journal.pgen.1006260

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Osteoarthritis is one of the most frequent and disabling diseases of the elderly. Only few genetic variants have been identified for osteoarthritis, which is partly due to large phenotype heterogeneity. To reduce heterogeneity, we here examined cartilage thickness, one of the structural components of joint health. We conducted a genome-wide association study of minimal joint space width (mJSW), a proxy for cartilage thickness, in a discovery set of 13,013 participants from five different cohorts and replication in 8,227 individuals from seven independent cohorts. We identified five genome-wide significant (GWS, P <= 5.0x10(-8)) SNPs annotated to four distinct loci. In addition, we found two additional loci that were significantly replicated, but results of combined meta-analysis fell just below the genome wide significance threshold. The four novel associated genetic loci were located in/near TGFA (rs2862851), PIK3R1 (rs10471753), SLBP/FGFR3 (rs2236995), and TREH/DDX6 (rs496547), while the other two (DOT1L and SUPT3H/RUNX2) were previously identified. A systematic prioritization for underlying causal genes was performed using diverse lines of evidence. Exome sequencing data (n = 2,050 individuals) indicated that there were no rare exonic variants that could explain the identified associations. In addition, TGFA, FGFR3 and PIK3R1 were differentially expressed in OA cartilage lesions versus non-lesioned cartilage in the same individuals. In conclusion, we identified four novel loci (TGFA, PIK3R1, FGFR3 and TREH) and confirmed two loci known to be associated with cartilage thickness. The identified associations were not caused by rare exonic variants. This is the first report linking TGFA to human OA, which may serve as a new target for future therapies.

引用

页数：22

共 48 条

[1] Hundreds of variants clustered in genomic loci and biological pathways affect human height [J].

Allen, Hana Lango ;

Estrada, Karol ;

Lettre, Guillaume ;

Berndt, Sonja I. ;

Weedon, Michael N. ;

Rivadeneira, Fernando ;

Willer, Cristen J. ;

Jackson, Anne U. ;

Vedantam, Sailaja ;

Raychaudhuri, Soumya ;

Ferreira, Teresa ;

Wood, Andrew R. ;

Weyant, Robert J. ;

Segre, Ayellet V. ;

Speliotes, Elizabeth K. ;

Wheeler, Eleanor ;

Soranzo, Nicole ;

Park, Ju-Hyun ;

Yang, Jian ;

Gudbjartsson, Daniel ;

Heard-Costa, Nancy L. ;

Randall, Joshua C. ;

Qi, Lu ;

Smith, Albert Vernon ;

Maegi, Reedik ;

Pastinen, Tomi ;

Liang, Liming ;

Heid, Iris M. ;

Luan, Jian'an ;

Thorleifsson, Gudmar ;

Winkler, Thomas W. ;

Goddard, Michael E. ;

Lo, Ken Sin ;

Palmer, Cameron ;

Workalemahu, Tsegaselassie ;

Aulchenko, Yurii S. ;

Johansson, Asa ;

Zillikens, M. Carola ;

Feitosa, Mary F. ;

Esko, Tonu ;

Johnson, Toby ;

Ketkar, Shamika ;

Kraft, Peter ;

Mangino, Massimo ;

Prokopenko, Inga ;

Absher, Devin ;

Albrecht, Eva ;

Ernst, Florian ;

Glazer, Nicole L. ;

Hayward, Caroline .

NATURE, 2010, 467 (7317) :832-838

[2] Transforming growth factor a suppression of articular chondrocyte phenotype and Sox9 expression in a rat model of osteoarthritis [J].

Appleton, C. Thomas G. ;

Usmani, Shirine E. ;

Bernier, Suzanne M. ;

Aigner, Thomas ;

Beier, Frank .

ARTHRITIS AND RHEUMATISM, 2007, 56 (11) :3693-3705

[3] Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture [J].

Berndt, Sonja I. ;

Gustafsson, Stefan ;

Maegi, Reedik ;

Ganna, Andrea ;

Wheeler, Eleanor ;

Feitosa, Mary F. ;

Justice, Anne E. ;

Monda, Keri L. ;

Croteau-Chonka, Damien C. ;

Day, Felix R. ;

Esko, Tonu ;

Fall, Tove ;

Ferreira, Teresa ;

Gentilini, Davide ;

Jackson, Anne U. ;

Luan, Jian'an ;

Randall, Joshua C. ;

Vedantam, Sailaja ;

Willer, Cristen J. ;

Winkler, Thomas W. ;

Wood, Andrew R. ;

Workalemahu, Tsegaselassie ;

Hu, Yi-Juan ;

Lee, Sang Hong ;

Liang, Liming ;

Lin, Dan-Yu ;

Min, Josine L. ;

Neale, Benjamin M. ;

Thorleifsson, Gudmar ;

Yang, Jian ;

Albrecht, Eva ;

Amin, Najaf ;

Bragg-Gresham, Jennifer L. ;

Cadby, Gemma ;

den Heijer, Martin ;

Eklund, Niina ;

Fischer, Krista ;

Goel, Anuj ;

Hottenga, Jouke-Jan ;

Huffman, Jennifer E. ;

Jarick, Ivonne ;

Johansson, Asa ;

Johnson, Toby ;

Kanoni, Stavroula ;

Kleber, Marcus E. ;

Koenig, Inke R. ;

Kristiansson, Kati ;

Kutalik, Zoltn ;

Lamina, Claudia ;

Lecoeur, Cecile .

NATURE GENETICS, 2013, 45 (05) :501-U69

[4] The NIH Roadmap Epigenomics Mapping Consortium [J].

Bernstein, Bradley E. ;

Stamatoyannopoulos, John A. ;

Costello, Joseph F. ;

Ren, Bing ;

Milosavljevic, Aleksandar ;

Meissner, Alexander ;

Kellis, Manolis ;

Marra, Marco A. ;

Beaudet, Arthur L. ;

Ecker, Joseph R. ;

Farnham, Peggy J. ;

Hirst, Martin ;

Lander, Eric S. ;

Mikkelsen, Tarjei S. ;

Thomson, James A. .

NATURE BIOTECHNOLOGY, 2010, 28 (10) :1045-1048

[5] Genome-wide association and functional studies identify the DOT1L gene to be involved in cartilage thickness and hip osteoarthritis [J].

Betancourt, Martha C. Castano ;

Cailotto, Frederic ;

Kerkhof, Hanneke J. ;

Cornelis, Frederique M. F. ;

Doherty, Sally A. ;

Hart, Deborah J. ;

Hofman, Albert ;

Luyten, Frank P. ;

Maciewicz, Rose A. ;

Mangino, Massimo ;

Metrustry, Sarah ;

Muir, Kenneth ;

Peters, Marjolein J. ;

Rivadeneira, Fernando ;

Wheeler, Maggie ;

Zhang, Weiya ;

Arden, Nigel ;

Spector, Tim D. ;

Uitterlinden, Andre G. ;

Doherty, Michael ;

Lories, Rik J. U. ;

Valdes, Ana M. ;

van Meurs, Joyce B. J. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2012, 109 (21) :8218-8223

[6] Bone parameters across different types of hip osteoarthritis and their relationship to osteoporotic fracture risk [J].

Castano-Betancourt, Martha C. ;

Rivadeneira, Fernando ;

Bierma-Zeinstra, Sita ;

Kerkhof, Hanneke J. M. ;

Hofman, Albert ;

Uitterlinden, Andre G. ;

van Meurs, Joyce B. J. .

ARTHRITIS AND RHEUMATISM, 2013, 65 (03) :693-700

[7]

Consortium RE, INTEGRATIVE ANAL 111, DOI [10.1038/nature14248, DOI 10.1038/NATURE14248]

[8] Mutations in PIK3R1 Cause SHORT Syndrome [J].

Dyment, David A. ;

Smith, Amanda C. ;

Alcantara, Diana ;

Schwartzentruber, Jeremy A. ;

Basel-Vanagaite, Lina ;

Curry, Cynthia J. ;

Temple, I. Karen ;

Reardon, William ;

Mansour, Sahar ;

Haq, Mushfequr R. ;

Gilbert, Rodney ;

Lehmann, Ordan J. ;

Vanstone, Megan R. ;

Beaulieu, Chandree L. ;

Majewski, Jacek ;

Bulman, Dennis E. ;

O'Driscoll, Mark ;

Boycott, Kym M. ;

Innes, A. Micheil .

AMERICAN JOURNAL OF HUMAN GENETICS, 2013, 93 (01) :158-166

[9] Cbfa1 is a positive regulatory factor in chondrocyte maturation [J].

Enomoto, H ;

Enomoto-Iwamoto, M ;

Iwamoto, M ;

Nomura, S ;

Himeno, M ;

Kitamura, Y ;

Kishimoto, T ;

Komori, T .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (12) :8695-8702

[10] Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture [J].

Estrada, Karol ;

Styrkarsdottir, Unnur ;

Evangelou, Evangelos ;

Hsu, Yi-Hsiang ;

Duncan, Emma L. ;

Ntzani, Evangelia E. ;

Oei, Ling ;

Albagha, Omar M. E. ;

Amin, Najaf ;

Kemp, John P. ;

Koller, Daniel L. ;

Li, Guo ;

Liu, Ching-Ti ;

Minster, Ryan L. ;

Moayyeri, Alireza ;

Vandenput, Liesbeth ;

Willner, Dana ;

Xiao, Su-Mei ;

Yerges-Armstrong, Laura M. ;

Zheng, Hou-Feng ;

Alonso, Nerea ;

Eriksson, Joel ;

Kammerer, Candace M. ;

Kaptoge, Stephen K. ;

Leo, Paul J. ;

Thorleifsson, Gudmar ;

Wilson, Scott G. ;

Wilson, James F. ;

Aalto, Ville ;

Alen, Markku ;

Aragaki, Aaron K. ;

Aspelund, Thor ;

Center, Jacqueline R. ;

Dailiana, Zoe ;

Duggan, David J. ;

Garcia, Melissa ;

Garcia-Giralt, Natalia ;

Giroux, Sylvie ;

Hallmans, Goran ;

Hocking, Lynne J. ;

Husted, Lise Bjerre ;

Jameson, Karen A. ;

Khusainova, Rita ;

Kim, Ghi Su ;

Kooperberg, Charles ;

Koromila, Theodora ;

Kruk, Marcin ;

Laaksonen, Marika ;

Lacroix, Andrea Z. ;

Lee, Seung Hun .

NATURE GENETICS, 2012, 44 (05) :491-+

← 1 2 3 4 5 →