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2. The identification of distinct protective and susceptibility mechanisms for hip osteoarthritis: findings from a genome-wide association study meta-analysis of minimum joint space width and Mendelian randomisation cluster analyses

Author

Faber, Benjamin G, Frysz, Monika, Boer, Cindy G, Evans, Daniel S, Ebsim, Raja, Flynn, Kaitlyn A, Lundberg, Mischa, Southam, Lorraine, Hartley, April, Saunders, Fiona R, Lindner, Claudia, Gregory, Jennifer S, Aspden, Richard M, Lane, Nancy E, Harvey, Nicholas C, Evans, David M, Zeggini, Eleftheria, Davey Smith, George, Cootes, Timothy, Van Meurs, Joyce, Kemp, John P, and Tobias, Jonathan H

Subjects
Arthritis, Clinical Research, Genetics, Aging, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Musculoskeletal, Cartilage, Genome-wide association study, Mendelian randomisation, Osteoarthritis, Clinical Sciences, Public Health and Health Services, Clinical sciences, Epidemiology
Abstract

BackgroundHip minimum joint space width (mJSW) provides a proxy for cartilage thickness. This study aimed to conduct a genome-wide association study (GWAS) of mJSW to (i) identify new genetic determinants of mJSW and (ii) identify which mJSW loci convey hip osteoarthritis (HOA) risk and would therefore be of therapeutic interest.MethodsGWAS meta-analysis of hip mJSW derived from plain X-rays and DXA was performed, stratified by sex and adjusted for age and ancestry principal components. Mendelian randomisation (MR) and cluster analyses were used to examine causal effect of mJSW on HOA.Findings50,745 individuals were included in the meta-analysis. 42 SNPs, which mapped to 39 loci, were identified. Mendelian randomisation (MR) revealed little evidence of a causal effect of mJSW on HOA (ORIVW 0.98 [95% CI 0.82-1.18]). However, MR-Clust analysis suggested the null MR estimates reflected the net effect of two distinct causal mechanisms cancelling each other out, one of which was protective, whereas the other increased HOA susceptibility. For the latter mechanism, all loci were positively associated with height, suggesting mechanisms leading to greater height and mJSW increase the risk of HOA in later life.InterpretationsOne group of mJSW loci reduce HOA risk via increased mJSW, suggesting possible utility as targets for chondroprotective therapies. The second group of mJSW loci increased HOA risk, despite increasing mJSW, but were also positively related to height, suggesting they contribute to HOA risk via a growth-related mechanism.FundingPrimarily funded by the Medical Research Council and Wellcome Trust.

Published
2023

6. The identification of distinct protective and susceptibility mechanisms for hip osteoarthritis: findings from a genome-wide association study meta-analysis of minimum joint space width and Mendelian randomisation cluster analyses

Author

Faber, Benjamin G., Frysz, Monika, Boer, Cindy G., Evans, Daniel S., Ebsim, Raja, Flynn, Kaitlyn A., Lundberg, Mischa, Southam, Lorraine, Hartley, April, Saunders, Fiona R., Lindner, Claudia, Gregory, Jennifer S., Aspden, Richard M., Lane, Nancy E., Harvey, Nicholas C., Evans, David M., Zeggini, Eleftheria, Davey Smith, George, Cootes, Timothy, Van Meurs, Joyce, Kemp, John P., and Tobias, Jonathan H.

Published
2023
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7. A functional genomics approach reveals suggestive quantitative trait loci associated with combined TLR4 and BCP crystal-induced inflammation and osteoarthritis

Author

Klück, Viola, Boahen, Collins K., Kischkel, Brenda, Dos Santos, Jéssica C., Matzaraki, Vasiliki, Boer, Cindy G., van Meurs, Joyce B.J., Schraa, Kiki, Lemmers, Heidi, Dijkstra, Helga, Leask, Megan P., Merriman, Tony R., Crişan, Tania O., McCarthy, Geraldine M., Kumar, Vinod, and Joosten, Leo A.B.

Published
2023
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8. Genome-wide meta-analysis of 158,000 individuals of European ancestry identifies three loci associated with chronic back pain.

Author

Suri, Pradeep, Palmer, Melody R, Tsepilov, Yakov A, Freidin, Maxim B, Boer, Cindy G, Yau, Michelle S, Evans, Daniel S, Gelemanovic, Andrea, Bartz, Traci M, Nethander, Maria, Arbeeva, Liubov, Karssen, Lennart, Neogi, Tuhina, Campbell, Archie, Mellstrom, Dan, Ohlsson, Claes, Marshall, Lynn M, Orwoll, Eric, Uitterlinden, Andre, Rotter, Jerome I, Lauc, Gordan, Psaty, Bruce M, Karlsson, Magnus K, Lane, Nancy E, Jarvik, Gail P, Polasek, Ozren, Hochberg, Marc, Jordan, Joanne M, Van Meurs, Joyce BJ, Jackson, Rebecca, Nielson, Carrie M, Mitchell, Braxton D, Smith, Blair H, Hayward, Caroline, Smith, Nicholas L, Aulchenko, Yurii S, and Williams, Frances MK

Subjects
Humans, Back Pain, Intracellular Signaling Peptides and Proteins, DNA-Binding Proteins, Polymorphism, Single Nucleotide, Introns, European Continental Ancestry Group, Genome-Wide Association Study, SOXD Transcription Factors, Genetic Loci, Chronic Pain, Biomarkers, Tumor, DCC Receptor, Polymorphism, Single Nucleotide, Biomarkers, Tumor, Human Genome, Genetics, Aging, Pain Research, 2.1 Biological and endogenous factors, Developmental Biology
Abstract

Back pain is the #1 cause of years lived with disability worldwide, yet surprisingly little is known regarding the biology underlying this symptom. We conducted a genome-wide association study (GWAS) meta-analysis of chronic back pain (CBP). Adults of European ancestry were included from 15 cohorts in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and from the UK Biobank interim data release. CBP cases were defined as those reporting back pain present for ≥3-6 months; non-cases were included as comparisons ("controls"). Each cohort conducted genotyping using commercially available arrays followed by imputation. GWAS used logistic regression models with additive genetic effects, adjusting for age, sex, study-specific covariates, and population substructure. The threshold for genome-wide significance in the fixed-effect inverse-variance weighted meta-analysis was p

Published
2018

9. Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations

Author

Loughlin, John, Arden, Nigel, Birrell, Fraser, Carr, Andrew, Deloukas, Panos, Doherty, Michael, McCaskie, Andrew W., Ollier, William E.R., Rai, Ashok, Ralston, Stuart H., Spector, Tim D., Wallis, Gillian A., Martinsen, Amy E., Willer, Cristen, Fors, Egil Andreas, Mundal, Ingunn, Hagen, Knut, Nilsen, Kristian Bernhard, Lie, Marie Udnesseter, Børte, Sigrid, Brumpton, Ben, Nielsen, Jonas Bille, Fritsche, Lars G., Zhou, Wei, Heuch, Ingrid, Storheim, Kjersti, Tyrpenou, Evangelos, Koukakis, Athanasios, Chytas, Dimitrios, Evangelopoulos, Dimitrios Stergios, Efstathios, Chronopoulos, Pneumaticos, Spiros, Nikolaou, Vasileios S., Malizos, Konstantinos, Anastasopoulou, Lydia, Abecasis, Goncalo, Baras, Aris, Cantor, Michael, Coppola, Giovanni, Deubler, Andrew, Economides, Aris, Lotta, Luca A., Overton, John D., Reid, Jeffrey G., Shuldiner, Alan, Karalis, Katia, Siminovitch, Katherine, Beechert, Christina, Forsythe, Caitlin, Fuller, Erin D., Gu, Zhenhua, Lattari, Michael, Lopez, Alexander, Schleicher, Thomas D., Padilla, Maria Sotiropoulos, Widom, Louis, Wolf, Sarah E., Pradhan, Manasi, Manoochehri, Kia, Bai, Xiaodong, Balasubramanian, Suganthi, Boutkov, Boris, Eom, Gisu, Habegger, Lukas, Hawes, Alicia, Krasheninina, Olga, Lanche, Rouel, Mansfield, Adam J., Maxwell, Evan K., Nafde, Mona, O’Keeffe, Sean, Orelus, Max, Panea, Razvan, Polanco, Tommy, Rasool, Ayesha, Salerno, William, Staples, Jeffrey C., Li, Dadong, Sharma, Deepika, Banerjee, Ilanjana, Bovijn, Jonas, Locke, Adam, Verweij, Niek, Haas, Mary, Hindy, George, De, Tanima, Akbari, Parsa, Sosina, Olukayode, Ferreira, Manuel A.R., Jones, Marcus B., Mighty, Jason, LeBlanc, Michelle G., Mitnaul, Lyndon J., Boer, Cindy G., Hatzikotoulas, Konstantinos, Southam, Lorraine, Stefánsdóttir, Lilja, Zhang, Yanfei, Coutinho de Almeida, Rodrigo, Wu, Tian T., Zheng, Jie, Hartley, April, Teder-Laving, Maris, Skogholt, Anne Heidi, Terao, Chikashi, Zengini, Eleni, Alexiadis, George, Barysenka, Andrei, Bjornsdottir, Gyda, Gabrielsen, Maiken E., Gilly, Arthur, Ingvarsson, Thorvaldur, Johnsen, Marianne B., Jonsson, Helgi, Kloppenburg, Margreet, Luetge, Almut, Lund, Sigrun H., Mägi, Reedik, Mangino, Massimo, Nelissen, Rob R.G.H.H., Shivakumar, Manu, Steinberg, Julia, Takuwa, Hiroshi, Thomas, Laurent F., Tuerlings, Margo, Babis, George C., Cheung, Jason Pui Yin, Kang, Jae Hee, Kraft, Peter, Lietman, Steven A., Samartzis, Dino, Slagboom, P. Eline, Stefansson, Kari, Thorsteinsdottir, Unnur, Tobias, Jonathan H., Uitterlinden, André G., Winsvold, Bendik, Zwart, John-Anker, Davey Smith, George, Sham, Pak Chung, Thorleifsson, Gudmar, Gaunt, Tom R., Morris, Andrew P., Valdes, Ana M., Tsezou, Aspasia, Cheah, Kathryn S.E., Ikegawa, Shiro, Hveem, Kristian, Esko, Tõnu, Wilkinson, J. Mark, Meulenbelt, Ingrid, Lee, Ming Ta Michael, van Meurs, Joyce B.J., Styrkársdóttir, Unnur, and Zeggini, Eleftheria

Published
2021
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10. Life-Course Genome-wide Association Study Meta-analysis of Total Body BMD and Assessment of Age-Specific Effects

Author

Medina-Gomez, Carolina, Kemp, John P, Trajanoska, Katerina, Luan, Jian’an, Chesi, Alessandra, Ahluwalia, Tarunveer S, Mook-Kanamori, Dennis O, Ham, Annelies, Hartwig, Fernando P, Evans, Daniel S, Joro, Raimo, Nedeljkovic, Ivana, Zheng, Hou-Feng, Zhu, Kun, Atalay, Mustafa, Liu, Ching-Ti, Nethander, Maria, Broer, Linda, Porleifsson, Gudmar, Mullin, Benjamin H, Handelman, Samuel K, Nalls, Mike A, Jessen, Leon E, Heppe, Denise HM, Richards, J Brent, Wang, Carol, Chawes, Bo, Schraut, Katharina E, Amin, Najaf, Wareham, Nick, Karasik, David, Van der Velde, Nathalie, Ikram, M Arfan, Zemel, Babette S, Zhou, Yanhua, Carlsson, Christian J, Liu, Yongmei, McGuigan, Fiona E, Boer, Cindy G, Bønnelykke, Klaus, Ralston, Stuart H, Robbins, John A, Walsh, John P, Zillikens, M Carola, Langenberg, Claudia, Li-Gao, Ruifang, Williams, Frances MK, Harris, Tamara B, Akesson, Kristina, Jackson, Rebecca D, Sigurdsson, Gunnar, Heijer, Martin den, van der Eerden, Bram CJ, van de Peppel, Jeroen, Spector, Timothy D, Pennell, Craig, Horta, Bernardo L, Felix, Janine F, Zhao, Jing Hua, Wilson, Scott G, de Mutsert, Renée, Bisgaard, Hans, Styrkársdóttir, Unnur, Jaddoe, Vincent W, Orwoll, Eric, Lakka, Timo A, Scott, Robert, Grant, Struan FA, Lorentzon, Mattias, van Duijn, Cornelia M, Wilson, James F, Stefansson, Kari, Psaty, Bruce M, Kiel, Douglas P, Ohlsson, Claes, Ntzani, Evangelia, van Wijnen, Andre J, Forgetta, Vincenzo, Ghanbari, Mohsen, Logan, John G, Williams, Graham R, Bassett, JH Duncan, Croucher, Peter I, Evangelou, Evangelos, Uitterlinden, Andre G, Ackert-Bicknell, Cheryl L, Tobias, Jonathan H, Evans, David M, and Rivadeneira, Fernando

Subjects
Rare Diseases, Aging, Human Genome, Osteoporosis, Clinical Research, Genetics, Aetiology, 2.1 Biological and endogenous factors, Musculoskeletal, Good Health and Well Being, Adolescent, Age Factors, Animals, Bone Density, Child, Child, Preschool, Genetic Loci, Genome-Wide Association Study, Humans, Infant, Infant, Newborn, Mice, Knockout, Polymorphism, Single Nucleotide, Quantitative Trait, Heritable, Regression Analysis, BMD, CREB3L1, ESR1, GWASs, RANKL, age-dependent effects, bone mineral density, fracture, genetic correlation, genome-wide association studies, meta-regression, total-body DXA, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Bone mineral density (BMD) assessed by DXA is used to evaluate bone health. In children, total body (TB) measurements are commonly used; in older individuals, BMD at the lumbar spine (LS) and femoral neck (FN) is used to diagnose osteoporosis. To date, genetic variants in more than 60 loci have been identified as associated with BMD. To investigate the genetic determinants of TB-BMD variation along the life course and test for age-specific effects, we performed a meta-analysis of 30 genome-wide association studies (GWASs) of TB-BMD including 66,628 individuals overall and divided across five age strata, each spanning 15 years. We identified variants associated with TB-BMD at 80 loci, of which 36 have not been previously identified; overall, they explain approximately 10% of the TB-BMD variance when combining all age groups and influence the risk of fracture. Pathway and enrichment analysis of the association signals showed clustering within gene sets implicated in the regulation of cell growth and SMAD proteins, overexpressed in the musculoskeletal system, and enriched in enhancer and promoter regions. These findings reveal TB-BMD as a relevant trait for genetic studies of osteoporosis, enabling the identification of variants and pathways influencing different bone compartments. Only variants in ESR1 and close proximity to RANKL showed a clear effect dependency on age. This most likely indicates that the majority of genetic variants identified influence BMD early in life and that their effect can be captured throughout the life course.

Published
2018

12. Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis.

Author

Castaño-Betancourt, Martha C, Evans, Dan S, Ramos, Yolande FM, 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 GHH, 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, and van Meurs, Joyce BJ

Subjects
Cartilage, Hip Joint, Humans, Osteoarthritis, Hip, Genetic Predisposition to Disease, Trehalase, Transforming Growth Factor alpha, Regulatory Sequences, Nucleic Acid, Genetic Heterogeneity, Polymorphism, Single Nucleotide, Aged, Aged, 80 and over, Middle Aged, Female, Male, Receptor, Fibroblast Growth Factor, Type 3, Genome-Wide Association Study, Phosphatidylinositol 3-Kinases, Class Ia Phosphatidylinositol 3-Kinase, Osteoarthritis, Hip, Regulatory Sequences, Nucleic Acid, Polymorphism, Single Nucleotide, and over, Receptor, Fibroblast Growth Factor, Type 3, Genetics, Developmental Biology
Abstract

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≤5·0×10-8) 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.

Published
2016

13. Cohort profile: Worldwide Collaboration on OsteoArthritis prediCtion for the Hip (World COACH) – an international consortium of prospective cohort studies with individual participant data on hip osteoarthritis

Author

UMC Utrecht Holding, ORT Research, Other research (not in main researchprogram), MS Orthopaedie Algemeen, Regenerative Medicine and Stem Cells, van Buuren, Michiel M.A., Riedstra, Noortje S., van den Berg, Myrthe A., Boel, Fleur D.E.M., Ahedi, Harbeer, Arbabi, Vahid, Arden, Nigel K., Bierma-Zeinstra, Sita M.A., Boer, Cindy G., Cicuttini, Flavia, Cootes, Timothy F., Crossley, Kay, Felson, David, Gielis, Willem Paul, Heerey, Joshua, Jones, Graeme, Kluzek, Stefan, Lane, Nancy E., Lindner, Claudia, Lynch, John A., Van Meurs, J., Mosler, Andrea B., Nelson, Amanda E., Nevitt, M., Oei, Edwin, Runhaar, Jos, Tang, Jinchi, Weinans, Harrie, Agricola, Rintje, UMC Utrecht Holding, ORT Research, Other research (not in main researchprogram), MS Orthopaedie Algemeen, Regenerative Medicine and Stem Cells, van Buuren, Michiel M.A., Riedstra, Noortje S., van den Berg, Myrthe A., Boel, Fleur D.E.M., Ahedi, Harbeer, Arbabi, Vahid, Arden, Nigel K., Bierma-Zeinstra, Sita M.A., Boer, Cindy G., Cicuttini, Flavia, Cootes, Timothy F., Crossley, Kay, Felson, David, Gielis, Willem Paul, Heerey, Joshua, Jones, Graeme, Kluzek, Stefan, Lane, Nancy E., Lindner, Claudia, Lynch, John A., Van Meurs, J., Mosler, Andrea B., Nelson, Amanda E., Nevitt, M., Oei, Edwin, Runhaar, Jos, Tang, Jinchi, Weinans, Harrie, and Agricola, Rintje

Published
2024

14. Cohort profile:Worldwide Collaboration on OsteoArthritis prediCtion for the Hip (World COACH) - an international consortium of prospective cohort studies with individual participant data on hip osteoarthritis

Author

van Buuren, Michiel M.A., Riedstra, Noortje S., van den Berg, Myrthe A., Boel, Fleur D.E.M., Ahedi, Harbeer, Arbabi, Vahid, Arden, Nigel K., Bierma-Zeinstra, Sita M.A., Boer, Cindy G., Cicuttini, Flavia, Cootes, Timothy F., Crossley, Kay, Felson, David, Gielis, Willem Paul, Heerey, Joshua, Jones, Graeme, Kluzek, Stefan, Lane, Nancy E., Lindner, Claudia, Lynch, John A., Van Meurs, J., Mosler, Andrea B., Nelson, Amanda E., Nevitt, M., Oei, Edwin, Runhaar, Jos, Tang, Jinchi, Weinans, Harrie, Agricola, Rintje, van Buuren, Michiel M.A., Riedstra, Noortje S., van den Berg, Myrthe A., Boel, Fleur D.E.M., Ahedi, Harbeer, Arbabi, Vahid, Arden, Nigel K., Bierma-Zeinstra, Sita M.A., Boer, Cindy G., Cicuttini, Flavia, Cootes, Timothy F., Crossley, Kay, Felson, David, Gielis, Willem Paul, Heerey, Joshua, Jones, Graeme, Kluzek, Stefan, Lane, Nancy E., Lindner, Claudia, Lynch, John A., Van Meurs, J., Mosler, Andrea B., Nelson, Amanda E., Nevitt, M., Oei, Edwin, Runhaar, Jos, Tang, Jinchi, Weinans, Harrie, and Agricola, Rintje

Abstract

Purpose Hip osteoarthritis (OA) is a major cause of pain and disability worldwide. Lack of effective therapies may reflect poor knowledge on its aetiology and risk factors, and result in the management of end-stage hip OA with costly joint replacement. The Worldwide Collaboration on OsteoArthritis prediCtion for the Hip (World COACH) consortium was established to pool and harmonise individual participant data from prospective cohort studies. The consortium aims to better understand determinants and risk factors for the development and progression of hip OA, to optimise and automate methods for (imaging) analysis, and to develop a personalised prediction model for hip OA. Participants World COACH aimed to include participants of prospective cohort studies with ≥200 participants, that have hip imaging data available from at least 2 time points at least 4 years apart. All individual participant data, including clinical data, imaging (data), biochemical markers, questionnaires and genetic data, were collected and pooled into a single, individual-level database. Findings to date World COACH currently consists of 9 cohorts, with 38 021 participants aged 18–80 years at baseline. Overall, 71% of the participants were women and mean baseline age was 65.3±8.6 years. Over 34 000 participants had baseline pelvic radiographs available, and over 22 000 had an additional pelvic radiograph after 8–12 years of follow-up. Even longer radiographic follow-up (15–25 years) is available for over 6000 of these participants.

Published
2024

17. Genome-wide analyses using UK Biobank data provide insights into the genetic architecture of osteoarthritis

Author

Zengini, Eleni, Hatzikotoulas, Konstantinos, Tachmazidou, Ioanna, Steinberg, Julia, Hartwig, Fernando P., Southam, Lorraine, Hackinger, Sophie, Boer, Cindy G., Styrkarsdottir, Unnur, Gilly, Arthur, Suveges, Daniel, Killian, Britt, Ingvarsson, Thorvaldur, Jonsson, Helgi, Babis, George C., McCaskie, Andrew, Uitterlinden, Andre G., van Meurs, Joyce B. J., Thorsteinsdottir, Unnur, Stefansson, Kari, Davey Smith, George, Wilkinson, Jeremy M., and Zeggini, Eleftheria

Published
2018
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19. Diversity, compositional and functional differences between gut microbiota of children and adults

Author

Radjabzadeh, Djawad, Boer, Cindy G., Beth, Sanne A., van der Wal, Pelle, Kiefte-De Jong, Jessica C., Jansen, Michelle A. E., Konstantinov, Sergey R., Peppelenbosch, Maikel P., Hays, John P., Jaddoe, Vincent W. V., Ikram, M. Arfan, Rivadeneira, Fernando, van Meurs, Joyce B. J., Uitterlinden, André G., Medina-Gomez, Carolina, Moll, Henriette A., and Kraaij, Robert

Published
2020
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21. Publisher Correction: GWAS of bone size yields twelve loci that also affect height, BMD, osteoarthritis or fractures

Author

Styrkarsdottir, Unnur, Stefansson, Olafur A., Gunnarsdottir, Kristbjorg, Thorleifsson, Gudmar, Lund, Sigrun H., Stefansdottir, Lilja, Juliusson, Kristinn, Agustsdottir, Arna B., Zink, Florian, Halldorsson, Gisli H., Ivarsdottir, Erna V., Benonisdottir, Stefania, Jonsson, Hakon, Gylfason, Arnaldur, Norland, Kristjan, Trajanoska, Katerina, Boer, Cindy G., Southam, Lorraine, Leung, Jason C. S., Tang, Nelson L. S., Kwok, Timothy C. Y., Lee, Jenny S. W., Ho, Suzanne C., Byrjalsen, Inger, Center, Jacqueline R., Lee, Seung Hun, Koh, Jung-Min, Lohmander, L. Stefan, Ho-Pham, Lan T., Nguyen, Tuan V., Eisman, John A., Woo, Jean, Leung, Ping-C., Loughlin, John, Zeggini, Eleftheria, Christiansen, Claus, Rivadeneira, Fernando, van Meurs, Joyce, Uitterlinden, Andre G., Mogensen, Brynjolfur, Jonsson, Helgi, Ingvarsson, Thorvaldur, Sigurdsson, Gunnar, Benediktsson, Rafn, Sulem, Patrick, Jonsdottir, Ingileif, Masson, Gisli, Holm, Hilma, Norddahl, Gudmundur L., Thorsteinsdottir, Unnur, Gudbjartsson, Daniel F., and Stefansson, Kari

Published
2019
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22. GWAS of bone size yields twelve loci that also affect height, BMD, osteoarthritis or fractures

Author

Styrkarsdottir, Unnur, Stefansson, Olafur A., Gunnarsdottir, Kristbjorg, Thorleifsson, Gudmar, Lund, Sigrun H., Stefansdottir, Lilja, Juliusson, Kristinn, Agustsdottir, Arna B., Zink, Florian, Halldorsson, Gisli H., Ivarsdottir, Erna V., Benonisdottir, Stefania, Jonsson, Hakon, Gylfason, Arnaldur, Norland, Kristjan, Trajanoska, Katerina, Boer, Cindy G., Southam, Lorraine, Leung, Jason C. S., Tang, Nelson L. S., Kwok, Timothy C. Y., Lee, Jenny S. W., Ho, Suzanne C., Byrjalsen, Inger, Center, Jacqueline R., Lee, Seung Hun, Koh, Jung-Min, Lohmander, L. Stefan, Ho-Pham, Lan T., Nguyen, Tuan V., Eisman, John A., Woo, Jean, Leung, Ping-C., Loughlin, John, Zeggini, Eleftheria, Christiansen, Claus, Rivadeneira, Fernando, van Meurs, Joyce, Uitterlinden, Andre G., Mogensen, Brynjolfur, Jonsson, Helgi, Ingvarsson, Thorvaldur, Sigurdsson, Gunnar, Benediktsson, Rafn, Sulem, Patrick, Jonsdottir, Ingileif, Masson, Gisli, Holm, Hilma, Norddahl, Gudmundur L., Thorsteinsdottir, Unnur, Gudbjartsson, Daniel F., and Stefansson, Kari

Published
2019
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23. The identification of distinct protective and susceptibility mechanisms for hip osteoarthritis:findings from a genome-wide association study meta-analysis of minimum joint space width and Mendelian randomisation cluster analyses

Author

Faber, Benjamin G., Frysz, Monika, Boer, Cindy G., Evans, Daniel S., Ebsim, Raja, Flynn, Kaitlyn A., Lundberg, Mischa, Southam, Lorraine, Hartley, April, Saunders, Fiona R., Lindner, Claudia, Gregory, Jennifer S., Aspden, Richard M., Lane, Nancy E., Harvey, Nicholas C., Evans, David M., Zeggini, Eleftheria, Davey Smith, George, Cootes, Timothy, Van Meurs, Joyce, Kemp, John P., Tobias, Jonathan H., Faber, Benjamin G., Frysz, Monika, Boer, Cindy G., Evans, Daniel S., Ebsim, Raja, Flynn, Kaitlyn A., Lundberg, Mischa, Southam, Lorraine, Hartley, April, Saunders, Fiona R., Lindner, Claudia, Gregory, Jennifer S., Aspden, Richard M., Lane, Nancy E., Harvey, Nicholas C., Evans, David M., Zeggini, Eleftheria, Davey Smith, George, Cootes, Timothy, Van Meurs, Joyce, Kemp, John P., and Tobias, Jonathan H.

Abstract

Background: Hip minimum joint space width (mJSW) provides a proxy for cartilage thickness. This study aimed to conduct a genome-wide association study (GWAS) of mJSW to (i) identify new genetic determinants of mJSW and (ii) identify which mJSW loci convey hip osteoarthritis (HOA) risk and would therefore be of therapeutic interest. Methods: GWAS meta-analysis of hip mJSW derived from plain X-rays and DXA was performed, stratified by sex and adjusted for age and ancestry principal components. Mendelian randomisation (MR) and cluster analyses were used to examine causal effect of mJSW on HOA. Findings: 50,745 individuals were included in the meta-analysis. 42 SNPs, which mapped to 39 loci, were identified. Mendelian randomisation (MR) revealed little evidence of a causal effect of mJSW on HOA (ORIVW 0.98 [95% CI 0.82–1.18]). However, MR-Clust analysis suggested the null MR estimates reflected the net effect of two distinct causal mechanisms cancelling each other out, one of which was protective, whereas the other increased HOA susceptibility. For the latter mechanism, all loci were positively associated with height, suggesting mechanisms leading to greater height and mJSW increase the risk of HOA in later life. Interpretations: One group of mJSW loci reduce HOA risk via increased mJSW, suggesting possible utility as targets for chondroprotective therapies. The second group of mJSW loci increased HOA risk, despite increasing mJSW, but were also positively related to height, suggesting they contribute to HOA risk via a growth-related mechanism. Funding: Primarily funded by the Medical Research Council and Wellcome Trust.

Published
2023

24. Plasma proteomics identifies CRTAC1 as a biomarker for osteoarthritis severity and progression

Author

Szilagyi, Ingrid A, Vallerga, Costanza L, Boer, Cindy G, Schiphof, Dieuwke, Ikram, M Arfan, Bierma-Zeinstra, Sita M A, van Meurs, Joyce B J, Szilagyi, Ingrid A, Vallerga, Costanza L, Boer, Cindy G, Schiphof, Dieuwke, Ikram, M Arfan, Bierma-Zeinstra, Sita M A, and van Meurs, Joyce B J

Abstract

Objectives: The aim of this study was to identify biomarkers for radiographic OA severity and progression acting within the inflammation and metabolic pathways. Methods: For 3517 Rotterdam Study participants, 184 plasma protein levels were measured using Olink inflammation and cardiometabolic panels. We studied associations with severity and progression of knee, hip and hand OA and a composite overall OA burden score by multivariable regression models, adjusting for age, sex, cell counts and BMI. Results: We found 18 significantly associated proteins for overall OA burden, of which 5 stayed significant after multiple testing correction: circulating cartilage acidic protein 1 (CRTAC1), cartilage oligomeric matrix protein (COMP), thrombospondin 4, IL-18 receptor 1 (IL-18R1) and TNF ligand superfamily member 14. These proteins were also associated with progression of knee OA, with the exception of IL-18R1. The strongest association was found for the level of CRTAC1, with 1 s.d. increase in protein level resulting in an increase of 0.09 (95% CI 0.06, 0.12) in the overall OA Kellgren-Lawrence sum score (P = 2.9 × 10-8) in the model adjusted for age, sex, BMI and cell counts. This association was also present with the severity of OA in all three joints and progression of knee OA and was independent of BMI. We observed a stronger association for CRTAC1 with OA than for the well-known OA biomarker COMP. Conclusion: We identified several compelling biomarkers reflecting the overall OA burden and the increased risk for OA progression. CRTAC1 was the most compelling and robust biomarker for OA severity and progression. Such a biomarker may be used for disease monitoring.

Published
2023

25. A Genome‐Wide Association Study Meta‐Analysis of Alpha Angle Suggests Cam‐Type Morphology May Be a Specific Feature of Hip Osteoarthritis in Older Adults

Author

Faber, Benjamin G., primary, Frysz, Monika, additional, Hartley, April E., additional, Ebsim, Raja, additional, Boer, Cindy G., additional, Saunders, Fiona R., additional, Gregory, Jennifer S., additional, Aspden, Richard M., additional, Harvey, Nicholas C., additional, Southam, Lorraine, additional, Giles, William, additional, Le Maitre, Christine L., additional, Wilkinson, J. Mark, additional, van Meurs, Joyce B. J., additional, Zeggini, Eleftheria, additional, Cootes, Timothy, additional, Lindner, Claudia, additional, Kemp, John P., additional, Davey Smith, George, additional, and Tobias, Jonathan H., additional

Published
2023
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26. Hip joint space width is causally related to hip osteoarthritis risk via distinct protective and susceptibility mechanisms: findings from a genome-wide association study meta-analysis

Author

Frysz, Monika, primary, Faber, Benjamin G., additional, Boer, Cindy G., additional, Evans, Daniel S., additional, Ebsim, Raja, additional, Flynn, Kaitlyn A., additional, Lundberg, Mischa, additional, Southam, Lorraine, additional, Hartley, April, additional, Saunders, Fiona R., additional, Lindner, Claudia, additional, Gregory, Jennifer S., additional, Aspden, Richard M., additional, Lane, Nancy E., additional, Harvey, Nicholas C., additional, Evans, David M., additional, Zeggini, Eleftheria, additional, Smith, George Davey, additional, Cootes, Timothy, additional, Van Meurs, Joyce, additional, Kemp, John P., additional, and Tobias, Jonathan H., additional

Published
2023
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27. A GWAS meta-analysis of alpha angle suggests cam-type morphology may be a specific feature of hip osteoarthritis in older adults

Author

Faber, Benjamin G., Frysz, Monika, Hartley, April E., Ebsim, Raja, Boer, Cindy G., Saunders, Fiona R., Gregory, Jennifer S., Aspden, Richard M., Harvey, Nicholas C., Southam, Lorraine, Giles, William, Le Maitre, Christine L., Wilkinson, J. Mark, van Meurs, Joyce B.J., Zeggini, Eleftheria, Cootes, Timothy, Lindner, Claudia, Kemp, John P., Davey Smith, George, and Tobias, Jonathan H.

Abstract

Objectives: To examine the genetic architecture of cam morphology, using alpha angle (AA) as a proxy measure, we conducted an AA genome wide association study (GWAS), followed by Mendelian randomisation (MR) to evaluate its causal relationship with hip osteoarthritis (HOA).Methods: Observational analyses examined associations between AA derived from hip DXA scans in UK Biobank (UKB), and radiographic HOA (rHOA) and subsequent total hip replacement (THR). Afterwards, an AA GWAS meta-analysis was performed (n=44,214), using AA previously derived in the Rotterdam Study (RS). Linkage disequilibrium score regression assessed the genetic correlation between AA and HOA. Genetic associations with PResults: DXA-derived AA showed expected associations between AA and rHOA (OR 1.63 [95% CI 1.58-1.67]) and THR (HR 1.45 [1.33-1.59]) in UKB. The heritability of AA was 10% and AA had a moderate genetic correlation with HOA (rg =0.26 [0.10-0.43]). Eight independent genetic signals were associated with AA. Two-sample MR provided weak evidence of causal effects of AA on HOA risk (inverse variance weighted (IVW): OR=1.84 [1.14-2.96], P 0.01). In contrast, genetic predisposition for HOA had stronger evidence of a causal effect on increased AA (IVW: β=0.09 [0.04-0.13], P 4.58 x 10-05 ).Conclusions: Expected observational associations between AA and related clinical outcomes provided face-validity for the DXA-derived AA measures. Evidence of bidirectional associations between AA and HOA, particularly in the reverse direction, suggests that hip shape modelling secondary to a genetic predisposition to HOA contributes to the well-established relationship between HOA and cam morphology in older adults.

Published
2023

28. Rare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology

Author

Bjornsdottir, Gyda, Stefánsdóttir, Lilja, Thorleifsson, Gudmar, Sulem, Patrick, Norland, Kristjan, Ferkingstad, Egil, Oddsson, Asmundur, Zink, Florian, Lund, Sigrun H., Nawaz, Muhammad S., Bragi Walters, G., Skuladottir, Astros Th., Gudjonsson, Sigurjon A., Einarsson, Gudmundur, Halldorsson, Gisli H., Bjarnadottir, Valgerdur, Sveinbjornsson, Gardar, Helgadottir, Anna, Styrkársdóttir, Unnur, Gudmundsson, Larus J., Pedersen, Ole B., Hansen, Thomas Folkmann, Werge, Thomas, Banasik, Karina, Troelsen, Anders, Skou, Soren T., Thørner, Lise Wegner, Erikstrup, Christian, Nielsen, Kaspar Rene, Mikkelsen, Susan, Andersen, Steffen, Brunak, Søren, Burgdorf, Kristoffer, Hjalgrim, Henrik, Jemec, Gregor, Jennum, Poul, Johansson, Per Ingemar, Nielsen, Kasper Rene, Nyegaard, Mette, Bruun, Mie Topholm, Pedersen, Ole Birger, Dinh, Khoa Manh, Sørensen, Erik, Ostrowski, Sisse R., Johansson, Pär Ingemar, Gudbjartsson, Daniel F., Stefansson, Hreinn, Þorsteinsdóttir, Unnur, Larsen, Margit Anita Hørup, Didriksen, Maria, Sækmose, Susanne, Zeggini, Eleftheria, Hatzikotoulas, Konstantinos, Southam, Lorraine, Gilly, Arthur, Barysenka, Andrei, van Meurs, Joyce B. J., Boer, Cindy G., Uitterlinden, André G., Jonsson, Helgi, Ingvarsson, Thorvaldur, Esko, Tõnu, Mägi, Reedik, Teder-Laving, Maris, Ikegawa, Shiro, Terao, Chikashi, Takuwa, Hiroshi, Meulenbelt, Ingrid, Coutinho de Almeida, Rodrigo, Kloppenburg, Margreet, Tuerlings, Margo, Slagboom, P. Eline, Nelissen, Rob R. G. H. H., Valdes, Ana M., Mangino, Massimo, Tsezou, Aspasia, Zengini, Eleni, Alexiadis, George, Babis, George C., Cheah, Kathryn S. E., Wu, Tian T., Samartzis, Dino, Cheung, Jason Pui Yin, Sham, Pak Chung, Kraft, Peter, Kang, Jae Hee, Hveem, Kristian, Zwart, John-Anker, Luetge, Almut, Skogholt, Anne Heidi, Johnsen, Marianne B., Thomas, Laurent F., Winsvold, Bendik, Gabrielsen, Maiken E., Lee, Ming Ta Michael, Zhang, Yanfei, Lietman, Steven A., Shivakumar, Manu, Smith, George Davey, Tobias, Jonathan H., Hartley, April, Gaunt, Tom R., Zheng, Jie, Wilkinson, J. Mark, Steinberg, Julia, Morris, Andrew P., Jonsdottir, Ingileif, Bjornsson, Aron, Olafsson, Ingvar H., Ulfarsson, Elfar, Blondal, Josep, Vikingsson, Arnor, Brunak, Soren, Ullum, Henrik, Thorsteinsdottir, Unnur, Thorgeirsson, Thorgeir E., Stefansson, Kari, Consortium, DBDS Genetic, Consortium, GO, and Internal Medicine

Subjects
Science, General Physics and Astronomy, Intervertebral Disc Degeneration, Intervertebral Disc/metabolism, Bone and Bones/metabolism, Bone and Bones, General Biochemistry, Genetics and Molecular Biology, health services administration, Humans, Sodium Sulfate Cotransporter/genetics, Intervertebral Disc, 3' Untranslated Regions, health care economics and organizations, Sodium Sulfate Cotransporter, Symporters/genetics, Multidisciplinary, Symporters, Sulfates, General Chemistry, equipment and supplies, Intervertebral Disc Degeneration/genetics, Intervertebral Disc Displacement/genetics, Sulfates/metabolism, population characteristics, human activities, Intervertebral Disc Displacement, Genome-Wide Association Study
Abstract

Back pain is a common and debilitating disorder with largely unknown underlying biology. Here we report a genome-wide association study of back pain using diagnoses assigned in clinical practice; dorsalgia (119,100 cases, 909,847 controls) and intervertebral disc disorder (IDD) (58,854 cases, 922,958 controls). We identify 41 variants at 33 loci. The most significant association (ORIDD = 0.92, P = 1.6 × 10−39; ORdorsalgia = 0.92, P = 7.2 × 10−15) is with a 3’UTR variant (rs1871452-T) in CHST3, encoding a sulfotransferase enzyme expressed in intervertebral discs. The largest effects on IDD are conferred by rare (MAF = 0.07 − 0.32%) loss-of-function (LoF) variants in SLC13A1, encoding a sodium-sulfate co-transporter (LoF burden OR = 1.44, P = 3.1 × 10−11); variants that also associate with reduced serum sulfate. Genes implicated by this study are involved in cartilage and bone biology, as well as neurological and inflammatory processes.

Published
2022
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29. Using multivariable Mendelian randomization to estimate the causal effect of bone mineral density on osteoarthritis risk, independently of body mass index

Author

Hartley, April, Sanderson, Eleanor, Granell, Raquel, Paternoster, Lavinia, Zheng, Jie, Smith, George Davey, Southam, Lorraine, Hatzikotoulas, Konstantinos, Boer, Cindy G., Van Meurs, Joyce, Zeggini, Eleftheria, Gregson, Celia L., Tobias, Jon H., Stefánsdóttir, Lilja, Zhang, Yanfei, De Almeida, Rodrigo Coutinho, Wu, Tian T., Teder-Laving, Maris, Skogholt, Anne Heidi, Terao, Chikashi, Zengini, Eleni, Alexiadis, George, Barysenka, Andrei, Bjornsdottir, Gyda, Gabrielsen, Maiken E., Gilly, Arthur, Ingvarsson, Thorvaldur, Johnsen, Marianne B., Jonsson, Helgi, Kloppenburg, Margreet G., Luetge, Almut, Mägi, Reedik, Mangino, Massimo, Nelissen, Rob R.G.H.H., Shivakumar, Manu, Steinberg, Julia, Takuwa, Hiroshi, Thomas, Laurent, Tuerlings, Margo, Babis, George, Cheung, Jason Pui Yin, Samartzis, Dino, Lietman, Steve A., Slagboom, P. Eline, Stefansson, Kari, Uitterlinden, André G., Winsvold, Bendik, Zwart, John Anker, Sham, Pak Chung, Thorleifsson, Gudmar, Gaunt, Tom R., Morris, Andrew P., Valdes, Ana M., Tsezou, Aspasia, Cheah, Kathryn S.E., Ikegawa, Shiro, Hveem, Kristian, Esko, Tõnu, Wilkinson, J. Mark, Meulenbelt, Ingrid, Michael Lee, Ming Ta, Styrkársdóttir, Unnur, and Internal Medicine

Subjects
Oncology, musculoskeletal diseases, medicine.medical_specialty, UK Biobank, Epidemiology, body mass index, Osteoarthritis, Polymorphism, Single Nucleotide, Genetic correlation, Body Mass Index, Mendelian Randomization, Uk Biobank, Bone Mineral Density, Bone Density, Internal medicine, Mendelian randomization, medicine, Humans, Allele, Risk factor, Bone mineral, business.industry, General Medicine, Mendelian Randomization Analysis, Osteoarthritis, Knee, medicine.disease, Causality, Observational study, business, bone mineral density, Body mass index, Genome-Wide Association Study
Abstract

Objectives Observational analyses suggest that high bone mineral density (BMD) is a risk factor for osteoarthritis (OA); it is unclear whether this represents a causal effect or shared aetiology and whether these relationships are body mass index (BMI)-independent. We performed bidirectional Mendelian randomization (MR) to uncover the causal pathways between BMD, BMI and OA. Methods One-sample (1S)MR estimates were generated by two-stage least-squares regression. Unweighted allele scores instrumented each exposure. Two-sample (2S)MR estimates were generated using inverse-variance weighted random-effects meta-analysis. Multivariable MR (MVMR), including BMD and BMI instruments in the same model, determined the BMI-independent causal pathway from BMD to OA. Latent causal variable (LCV) analysis, using weight-adjusted femoral neck (FN)–BMD and hip/knee OA summary statistics, determined whether genetic correlation explained the causal effect of BMD on OA. Results 1SMR provided strong evidence for a causal effect of BMD estimated from heel ultrasound (eBMD) on hip and knee OA {odds ratio [OR]hip = 1.28 [95% confidence interval (CI) = 1.05, 1.57], p = 0.02, ORknee = 1.40 [95% CI = 1.20, 1.63], p = 3 × 10–5, OR per standard deviation [SD] increase}. 2SMR effect sizes were consistent in direction. Results suggested that the causal pathways between eBMD and OA were bidirectional (βhip = 1.10 [95% CI = 0.36, 1.84], p = 0.003, βknee = 4.16 [95% CI = 2.74, 5.57], p = 8 × 10–9, β = SD increase per doubling in risk). MVMR identified a BMI-independent causal pathway between eBMD and hip/knee OA. LCV suggested that genetic correlation (i.e. shared genetic aetiology) did not fully explain the causal effects of BMD on hip/knee OA. Conclusions These results provide evidence for a BMI-independent causal effect of eBMD on OA. Despite evidence of bidirectional effects, the effect of BMD on OA did not appear to be fully explained by shared genetic aetiology, suggesting a direct action of bone on joint deterioration.

Published
2022
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30. Genome-wide association and functional studies identify a role for matrix Gla protein in osteoarthritis of the hand

Author

den Hollander, Wouter, Boer, Cindy G, Hart, Deborah J, Yau, Michelle S, Ramos, Yolande F M, Metrustry, Sarah, Broer, Linda, Deelen, Joris, Cupples, L Adrienne, Rivadeneira, Fernando, Kloppenburg, Margreet, Peters, Marjolein, Spector, Tim D, Hofman, Albert, Slagboom, P Eline, Nelissen, Rob G H H, Uitterlinden, André G, Felson, David T, Valdes, Ana M, Meulenbelt, Ingrid, and van Meurs, Joyce J B

Published
2017
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32. Risk Assessment for Hip and Knee Osteoarthritis Using Polygenic Risk Scores

Author

Sedaghati‐Khayat, Bahar, primary, Boer, Cindy G., additional, Runhaar, Jos, additional, Bierma‐Zeinstra, Sita M. A., additional, Broer, Linda, additional, Ikram, M. Arfan, additional, Zeggini, Eleftheria, additional, Uitterlinden, André G., additional, van Rooij, Jeroen G. J., additional, and van Meurs, Joyce B. J., additional

Published
2022
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33. Investigation of the genetic architecture of cam morphology, and its relationship with hip osteoarthritis, using alpha angle as a proxy measure

Author

Faber, Benjamin G., primary, Frysz, Monika, additional, Hartley, April E., additional, Ebsim, Raja, additional, Boer, Cindy G., additional, Saunders, Fiona R., additional, Gregory, Jennifer S., additional, Aspden, Richard M, additional, Harvey, Nicholas C., additional, Southam, Lorraine, additional, Giles, William, additional, Maitre, Christine Le, additional, Wilkinson, J. Mark, additional, van Meurs, Joyce B.J., additional, Zeggini, Eleftheria, additional, Cootes, Timothy, additional, Lindner, Claudia, additional, Kemp, John P., additional, Smith, George Davey, additional, and Tobias, Jonathan H., additional

Published
2022
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34. Bivariate genome-wide association meta-analysis of pediatric musculoskeletal traits reveals pleiotropic effects at the SREBF1/TOM1L2 locus

Author

Medina-Gomez, Carolina, Kemp, John P., Dimou, Niki L., Kreiner, Eskil, Chesi, Alessandra, Zemel, Babette S., Bønnelykke, Klaus, Boer, Cindy G., Ahluwalia, Tarunveer S., Bisgaard, Hans, Evangelou, Evangelos, Heppe, Denise H. M., Bonewald, Lynda F., Gorski, Jeffrey P., Ghanbari, Mohsen, Demissie, Serkalem, Duque, Gustavo, Maurano, Matthew T., Kiel, Douglas P., Hsu, Yi-Hsiang, C.J. van der Eerden, Bram, Ackert-Bicknell, Cheryl, Reppe, Sjur, Gautvik, Kaare M., Raastad, Truls, Karasik, David, van de Peppel, Jeroen, Jaddoe, Vincent W. V., Uitterlinden, André G., Tobias, Jonathan H., Grant, Struan F.A., Bagos, Pantelis G., Evans, David M., and Rivadeneira, Fernando

Published
2017
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35. Risk Assessment for Hip and Knee Osteoarthritis Using Polygenic Risk Scores

Author

Sedaghati-Khayat, Bahar, Boer, Cindy G., Runhaar, Jos, Bierma-Zeinstra, Sita M.A., Broer, Linda, Ikram, M. Arfan, Zeggini, Eleftheria, Uitterlinden, André G., van Rooij, Jeroen G.J., van Meurs, Joyce B.J., Sedaghati-Khayat, Bahar, Boer, Cindy G., Runhaar, Jos, Bierma-Zeinstra, Sita M.A., Broer, Linda, Ikram, M. Arfan, Zeggini, Eleftheria, Uitterlinden, André G., van Rooij, Jeroen G.J., and van Meurs, Joyce B.J.

Abstract

Objective: Polygenic risk scores (PRS) allow risk stratification using common single-nucleotide polymorphisms (SNPs), and clinical applications are currently explored for several diseases. This study was undertaken to assess the risk of hip and knee osteoarthritis (OA) using PRS. Methods: We analyzed 12,732 individuals from a population-based cohort from the Rotterdam Study (n = 11,496), a clinical cohort (Cohort Hip and Cohort Knee [CHECK] study; n = 908), and a high-risk cohort of overweight women (Prevention of Knee OA in Overweight Females [PROOF] study; n = 328), for the association of the PRS with prevalence/incidence of radiographic OA, of clinical OA, and of total hip replacement (THR) or total knee replacement (TKR). The hip PRS and knee PRS contained 44 and 24 independent SNPs, respectively, and were derived from a recent genome-wide association study meta-analysis. Standardized PRS (with Z transformation) were used in all analyses. Results: We found a stronger association of the PRS for clinically defined OA compared to radiographic OA phenotypes, and we observed the highest PRS risk stratification for TKR/THR. The odds ratio (OR) per SD was 1.3 for incident THR (95% confidence interval [95% CI] 1.1–1.5) and 1.6 (95% CI 1.3–1.9) for incident TKR in the Rotterdam Study. The knee PRS was associated with incident clinical knee OA in the CHECK study (OR 1.3 [95% CI 1.1–1.5]), but not for the PROOF study (OR 1.2 [95% CI 0.8–1.7]). The OR for OA increased gradually across the PRS distribution, up to 2.1 (95% CI 1.4–3.2) for individuals with the 10% highest PRS compared to the middle 50% of the PRS distribution. Conclusion: Our findings validated the association of PRS across OA definitions. Since OA is becoming frequent and primary prevention is not commonly applicable, PRS-based risk assessment could play a role in OA prevention. However, the utility of PRS is dependent on the setting. Further studies are needed to test the integration of genetic risk asses

Published
2022

36. Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations

Author

Boer, Cindy G., Hatzikotoulas, Konstantinos, Southam, Lorraine, Stefánsdóttir, Lilja, Zhang, Yanfei, Coutinho de Almeida, Rodrigo, Wu, Tian T., Zheng, Jie, Hartley, April, Teder-Laving, Maris, Skogholt, Anne Heidi, Terao, Chikashi, Zengini, Eleni, Alexiadis, George, Barysenka, Andrei, Bjornsdottir, Gyda, Gabrielsen, Maiken E., Gilly, Arthur, Ingvarsson, Thorvaldur, Johnsen, Marianne B., Jonsson, Helgi, Kloppenburg, Margreet, Luetge, Almut, Lund, Sigrun H., Mägi, Reedik, Mangino, Massimo, Nelissen, Rob R.G.H.H., Shivakumar, Manu, Steinberg, Julia, Takuwa, Hiroshi, Thomas, Laurent F., Tuerlings, Margo, Babis, George C., Cheung, Jason Pui Yin, Kang, Jae Hee, Kraft, Peter, Lietman, Steven A., Samartzis, Dino, Slagboom, P. Eline, Stefansson, Kari, Thorsteinsdottir, Unnur, Tobias, Jonathan H., Uitterlinden, André G., Winsvold, Bendik, Zwart, John-Anker, Davey Smith, George, Sham, Pak Chung, Thorleifsson, Gudmar, Gaunt, Tom R., Morris, Andrew P., Valdes, Ana M., Tsezou, Aspasia, Cheah, Kathryn S.E., Ikegawa, Shiro, Hveem, Kristian, Esko, Tõnu, Wilkinson, J. Mark, Meulenbelt, Ingrid, Lee, Ming Ta Michael, van Meurs, Joyce B.J., Styrkársdóttir, Unnur, and Zeggini, Eleftheria

Published
2021
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39. Vitamin K antagonist anticoagulant usage is associated with increased incidence and progression of osteoarthritis

Author

Boer, Cindy G., Szilagyi, Ingrid, Nguyen, N. Long, Neogi, Tuhina, Meulenbelt, Ingrid, Ikram, M. Arfan, Uitterlinden, André G., Bierma-Zeinstra, Sita, Stricker, Bruno H., Van Meurs, Joyce B., Boer, Cindy G., Szilagyi, Ingrid, Nguyen, N. Long, Neogi, Tuhina, Meulenbelt, Ingrid, Ikram, M. Arfan, Uitterlinden, André G., Bierma-Zeinstra, Sita, Stricker, Bruno H., and Van Meurs, Joyce B.

Abstract

Objectives Vitamin K is hypothesised to play a role in osteoarthritis (OA) pathogenesis through effects on vitamin K-dependent bone and cartilage proteins, and therefore may represent a modifiable risk factor. A genetic variant in a vitamin K-dependent protein that is an essential inhibitor for cartilage calcification, matrix Gla protein (MGP), was associated with an increased risk for OA. Vitamin K antagonist anticoagulants (VKAs), such as warfarin and acenocoumarol, act as anticoagulants through inhibition of vitamin K-dependent blood coagulation proteins. VKAs likely also affect the functioning of other vitamin K-dependent proteins such as MGP. Methods We investigated the effect of acenocoumarol usage on progression and incidence of radiographic OA in 3494 participants of the Rotterdam Study cohort. We also examined the effect of MGP and VKORC1 single nucleotide variantson this association. Results Acenocoumarol usage was associated with an increased risk of OA incidence and progression (OR=2.50, 95% CI=1.94-3.20), both for knee (OR=2.34, 95% CI=1.67-3.22) and hip OA (OR=2.74, 95% CI=1.82-4.11). Among acenocoumarol users, carriers of the high VKORC1(BB) expression haplotype together with the MGP OA risk allele (rs1800801-T) had an increased risk of OA incidence and progression (OR=4.18, 95% CI=2.69-6.50), while this relationship was not present in non-users of that group (OR=1.01, 95% CI=0.78-1.33). Conclusions These findings support the importance of vitamin K and vitamin K-dependent proteins, as MGP, in the pathogenesis of OA. Additionally, these results may have direct implications for the clinical prevention of OA, supporting the considerationof direct oral anticoagulants in favour of VKAs.

Published
2021

41. Genome-wide association and functional studies identify a role for matrix Gla protein in osteoarthritis of the hand

Author

Hollander, Wouter den, Boer, Cindy G., Hart, Deborah J., Yau, Michelle S., Ramos, Yolande F.M., Metrustry, Sarah, Broer, Linda, Deelen, Joris, Cupples, L. Adrienne, Rivadeneira, Fernando, Kloppenburg, Margreet, Peters, Marjolein, Spector, Tim D., Hofman, Albert, Slagboom, P. Eline, Nelissen, Rob G.H.H., Felson, David T., Valdes, Ana M., Meulenbelt, Ingrid, and van Meurs, Joyce J.B.

Subjects
nutritional and metabolic diseases
Abstract

Objective Osteoarthritis (OA) is the most common form of arthritis and the leading cause of disability in the elderly. Of all the joints, genetic predisposition is strongest for OA of the hand; however, only few genetic risk loci for hand OA have been identified. Our aim was to identify novel genes associated with hand OA and examine the underlying mechanism.Methods We performed a genome-wide association study of a quantitative measure of hand OA in 12 784 individuals (discovery: 8743, replication: 4011). Genome-wide significant signals were followed up by analysing gene and allele-specific expression in a RNA sequencing dataset (n=96) of human articular cartilage.Results We found two significantly associated loci in the discovery set: at chr12 (p=3.5 × 10⁻¹⁰) near the matrix Gla protein (MGP) gene and at chr12 (p=6.1×10⁻⁹) near the CCDC91 gene. The DNA variant near the MGP gene was validated in three additional studies, which resulted in a highly significant association between the MGP variant and hand OA (rs4764133, Betameta=0.83, Pmeta=1.8*10⁻¹⁵). This variant is high linkage disequilibrium with a coding variant in MGP, a vitamin K-dependent inhibitor of cartilage calcification. Using RNA sequencing data from human primary cartilage tissue (n=96), we observed that the MGP RNA expression of the hand OA risk allele was significantly lowercompared with the MGP RNA expression of the reference allele (40.7%, p

Published
2017

43. Genome-wide Meta-analysis of 158,000 Individuals of European Ancestry Identifies Three Loci Associated with Chronic Back Pain

Author

Suri, Pradeep, primary, Palmer, Melody R., additional, Tsepilov, Yakov A., additional, Freidin, Maxim B., additional, Boer, Cindy G., additional, Yau, Michelle S., additional, Evans, Daniel S., additional, Gelemanovic, Andrea, additional, Bartz, Traci M., additional, Nethander, Maria, additional, Arbeeva, Liubov, additional, Karssen, Lennart, additional, Neogi, Tuhina, additional, Campbell, Archie, additional, Mellstrom, Dan, additional, Ohlsson, Claes, additional, Marshall, Lynn M., additional, Orwoll, Eric, additional, Uitterlinden, Andre, additional, Rotter, Jerome I., additional, Lauc, Gordan, additional, Psaty, Bruce M., additional, Karlsson, Magnus K, additional, Lane, Nancy E., additional, Jarvik, Gail, additional, Polasek, Ozren, additional, Hochberg, Marc, additional, Jordan, Joanne M., additional, Van Meurs, Joyce B. J., additional, Jackson, Rebecca, additional, Nielson, Carrie M., additional, Mitchell, Braxton D., additional, Smith, Blair H., additional, Hayward, Caroline, additional, Smith, Nicholas L., additional, Aulchenko, Yurii S., additional, and Williams, Frances M.K., additional

Published
2018
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44. The genetic architecture of osteoarthritis: insights from UK Biobank

Author

Zengini, Eleni, primary, Hatzikotoulas, Konstantinos, additional, Tachmazidou, Ioanna, additional, Steinberg, Julia, additional, Hartwig, Fernando P., additional, Southam, Lorraine, additional, Hackinger, Sophie, additional, Boer, Cindy G., additional, Styrkarsdottir, Unnur, additional, Suveges, Daniel, additional, Killian, Britt, additional, Gilly, Arthur, additional, Ingvarsson, Thorvaldur, additional, Jonsson, Helgi, additional, Babis, George C., additional, McCaskie, Andrew, additional, Uitterlinden, Andre G., additional, van Meurs, Joyce B. J., additional, Thorsteinsdottir, Unnur, additional, Stefansson, Kari, additional, Smith, George Davey, additional, Wilkinson, Mark J., additional, and Zeggini, Eleftheria, additional

Published
2017
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46. Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis

Author

Castaño-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, Castaño-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., and van Meurs, Joyce B J

Published
2016

47. Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis

Author

Lab Reumatologie/Klinische Immunologie, Regenerative Medicine and Stem Cells, Infection & Immunity, dLAB Biobank, Castaño-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, Lab Reumatologie/Klinische Immunologie, Regenerative Medicine and Stem Cells, Infection & Immunity, dLAB Biobank, Castaño-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., and van Meurs, Joyce B J

Published
2016

48. Genome-wide association study identifies nine novel loci for 2D:4D finger ratio, a putative retrospective biomarker of testosterone exposure in utero.

Author

Warrington, Nicole M., Shevroja, Enisa, Hemani, Gibran, Hysi, Pirro G., Yunxuan Jiang, Auton, Adam, Boer, Cindy G., Mangino, Massimo, Wang, Carol A., Kemp, John P., McMahon, George, Medina-Gomez, Carolina, Hickey, Martha, Trajanoska, Katerina, Wolke, Dieter, Arfan Ikram, M., Montgomery, Grant W., Felix, Janine F., Wright, Margaret J., and Mackey, David A.

Published
2018
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49. Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis

Author

Yau, Michelle S., Lane, Nancy E., Barrett-Connor, Elizabeth, Valdes, Ana M., Lafeber, Floris, Muir, Kenneth, Evans, Dan S., Boer, Cindy G., Nelissen, Rob G. H. H., Uitterlinden, Andre G., Kraus, Virginia B., Zhang, Weiya, van Rooij, Jeroen, Rivadeneira, Fernando, Styrkarsdottir, Unnur, Kloppenburg, Margreet, Metrustry, Sarah, Castaño-Betancourt, Martha C., Hart, Deborah J., Ramos, Yolande F. M., Doherty, Michael, Spector, Tim D., Meulenbelt, Ingrid, Doherty, Sally, Liu, Youfang, Jordan, Joanne M., Hofman, Albert, Kraaij, Robert, Evangelou, Evangelos, Nevitt, Michael C., den Hollander, Wouter, van Meurs, Joyce B. J., Zeggini, Eleftheria, Slagboom, Eline P., Arden, Nigel, Mitchell, Braxton D., and Maciewicz, Rose A.

Subjects
3. Good health
Abstract

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≤5·0×10−8) 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.

50. Genome-wide association and functional studies identify a role for matrix Gla protein in osteoarthritis of the hand

Author

Hollander, Wouter den, Boer, Cindy G., Hart, Deborah J., Yau, Michelle S., Ramos, Yolande F.M., Metrustry, Sarah, Broer, Linda, Deelen, Joris, Cupples, L. Adrienne, Rivadeneira, Fernando, Kloppenburg, Margreet, Peters, Marjolein, Spector, Tim D., Hofman, Albert, Slagboom, P. Eline, Nelissen, Rob G.H.H., Uitterlinden, André G., Felson, David T., Valdes, Ana M., Meulenbelt, Ingrid, van Meurs, Joyce J.B., Hollander, Wouter den, Boer, Cindy G., Hart, Deborah J., Yau, Michelle S., Ramos, Yolande F.M., Metrustry, Sarah, Broer, Linda, Deelen, Joris, Cupples, L. Adrienne, Rivadeneira, Fernando, Kloppenburg, Margreet, Peters, Marjolein, Spector, Tim D., Hofman, Albert, Slagboom, P. Eline, Nelissen, Rob G.H.H., Uitterlinden, André G., Felson, David T., Valdes, Ana M., Meulenbelt, Ingrid, and van Meurs, Joyce J.B.

Abstract

Objective Osteoarthritis (OA) is the most common form of arthritis and the leading cause of disability in the elderly. Of all the joints, genetic predisposition is strongest for OA of the hand; however, only few genetic risk loci for hand OA have been identified. Our aim was to identify novel genes associated with hand OA and examine the underlying mechanism. Methods We performed a genome-wide association study of a quantitative measure of hand OA in 12 784 individuals (discovery: 8743, replication: 4011). Genome-wide significant signals were followed up by analysing gene and allele-specific expression in a RNA sequencing dataset (n=96) of human articular cartilage. Results We found two significantly associated loci in the discovery set: at chr12 (p=3.5 × 10⁻¹⁰) near the matrix Gla protein (MGP) gene and at chr12 (p=6.1×10⁻⁹) near the CCDC91 gene. The DNA variant near the MGP gene was validated in three additional studies, which resulted in a highly significant association between the MGP variant and hand OA (rs4764133, Betameta=0.83, Pmeta=1.8*10⁻¹⁵). This variant is high linkage disequilibrium with a coding variant in MGP, a vitamin K-dependent inhibitor of cartilage calcification. Using RNA sequencing data from human primary cartilage tissue (n=96), we observed that the MGP RNA expression of the hand OA risk allele was significantly lowercompared with the MGP RNA expression of the reference allele (40.7%, p<5*10⁻¹⁶). Conclusions Our results indicate that the association between the MGP variant and increased risk for hand OA is caused by a lower expression of MGP, which may increase the burden of hand OA by decreased inhibition of cartilage calcification.

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