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6. Prioritization ofPLECandGRINAas Osteoarthritis Risk Genes Through the Identification and Characterization of Novel Methylation Quantitative Trait Loci

Author

Rice, Sarah J., primary, Tselepi, Maria, additional, Sorial, Antony K., additional, Aubourg, Guillaume, additional, Shepherd, Colin, additional, Almarza, David, additional, Skelton, Andrew J., additional, Pangou, Ioanna, additional, Deehan, David, additional, Reynard, Louise N., additional, and Loughlin, John, additional

Published
2019
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11. Assessment of osteoarthritis candidate genes in a meta-analysis of nine genome-wide association studies

Author

Rodríguez-Fontenla, Cristina, Calaza, Manuel, Evangelou, Evangelos, Valdés, Ana M., Arden, Nigel, Blanco García, Francisco J, Carr, Andrew, Chapman, Kay, Deloukas, Panos, Doherty, Michael, Esko, Tonu, Garcés Aletá, Carlos M., Gómez-Reino Carnota, Juan J., Helgadottir, Hafids, Hofman, Albert, Jonsdottir, Ingilef, Kerkhof, Henneke J.M., Kloppenburg, Margreet, McCaskie, Andrew, Ntzani, Evangelia E., Ollier, William E.R., Oreiro, Natividad, Panoutsopoulo, Kalliope, Ralston, Stuart H., Ramos, Yolande F. M., Riancho, José A., Rivadeneira, Fernando, Slagboom, Eline, Styrkarsdottir, Unnur, Thorsteindottir, Unnur, Thorleifsson, Gudmar, Tsezou, Aspasia, Uitterlinden, André G., Wallis, Gillian A., Wilkinson, J. Mark, Zhai, Yanyan, Felson, David T., Ioannidis, John P.A., Loughlin, John, Metspalu, Andres, Meulenbelt, Ingrid, Stefansson, Kari, van Meurs, Joyce B., Zeggini, Eleftheria, Spector, Timothy D., González, Antonio, Rodríguez-Fontenla, Cristina, Calaza, Manuel, Evangelou, Evangelos, Valdés, Ana M., Arden, Nigel, Blanco García, Francisco J, Carr, Andrew, Chapman, Kay, Deloukas, Panos, Doherty, Michael, Esko, Tonu, Garcés Aletá, Carlos M., Gómez-Reino Carnota, Juan J., Helgadottir, Hafids, Hofman, Albert, Jonsdottir, Ingilef, Kerkhof, Henneke J.M., Kloppenburg, Margreet, McCaskie, Andrew, Ntzani, Evangelia E., Ollier, William E.R., Oreiro, Natividad, Panoutsopoulo, Kalliope, Ralston, Stuart H., Ramos, Yolande F. M., Riancho, José A., Rivadeneira, Fernando, Slagboom, Eline, Styrkarsdottir, Unnur, Thorsteindottir, Unnur, Thorleifsson, Gudmar, Tsezou, Aspasia, Uitterlinden, André G., Wallis, Gillian A., Wilkinson, J. Mark, Zhai, Yanyan, Felson, David T., Ioannidis, John P.A., Loughlin, John, Metspalu, Andres, Meulenbelt, Ingrid, Stefansson, Kari, van Meurs, Joyce B., Zeggini, Eleftheria, Spector, Timothy D., and González, Antonio

Abstract

[Abstract] Objective: To assess candidate genes for association with osteoarthritis (OA) and identify promising genetic factors and, secondarily, to assess the candidate gene approach in OA. Methods: A total of 199 candidate genes for association with OA were identified using Human Genome Epidemiology (HuGE) Navigator. All of their single-nucleotide polymorphisms (SNPs) with an allele frequency of >5% were assessed by fixed-effects meta-analysis of 9 genome-wide association studies (GWAS) that included 5,636 patients with knee OA and 16,972 control subjects and 4,349 patients with hip OA and 17,836 control subjects of European ancestry. An additional 5,921 individuals were genotyped for significantly associated SNPs in the meta-analysis. After correction for the number of independent tests, P values less than 1.58 × 10(-5) were considered significant. Results: SNPs at only 2 of the 199 candidate genes (COL11A1 and VEGF) were associated with OA in the meta-analysis. Two SNPs in COL11A1 showed association with hip OA in the combined analysis: rs4907986 (P = 1.29 × 10(-5) , odds ratio [OR] 1.12, 95% confidence interval [95% CI] 1.06-1.17) and rs1241164 (P = 1.47 × 10(-5) , OR 0.82, 95% CI 0.74-0.89). The sex-stratified analysis also showed association of COL11A1 SNP rs4908291 in women (P = 1.29 × 10(-5) , OR 0.87, 95% CI 0.82-0.92); this SNP showed linkage disequilibrium with rs4907986. A single SNP of VEGF, rs833058, showed association with hip OA in men (P = 1.35 × 10(-5) , OR 0.85, 95% CI 0.79-0.91). After additional samples were genotyped, association at one of the COL11A1 signals was reinforced, whereas association at VEGF was slightly weakened. Conclusion: Two candidate genes, COL11A1 and VEGF, were significantly associated with OA in this focused meta-analysis. The remaining candidate genes were not associated.

Published
2013

12. A new phenotype of brain iron accumulation with dystonia, optic atrophy, and peripheral neuropathy

Author

Horvath, Rita, primary, Holinski‐Feder, Elke, additional, Neeve, Vivienne C.M., additional, Pyle, Angela, additional, Griffin, Helen, additional, Ashok, Deephthi, additional, Foley, Charlotte, additional, Hudson, Gavin, additional, Rautenstrauss PhD, Bernd, additional, Nürnberg, Gudrun, additional, Nürnberg, Peter, additional, Kortler, Jörg, additional, Neitzel, Birgit, additional, Bäßmann, Ingelore, additional, Rahman, Thahira, additional, Keavney, Bernard, additional, Loughlin, John, additional, Hambleton, Sophie, additional, Schoser, Benedikt, additional, Lochmüller, Hanns, additional, Santibanez‐Koref, Mauro, additional, and Chinnery, Patrick F., additional

Published
2012
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13. A genome-wide association study identifies a locus on chromosome 7q22 to influence susceptibility for osteoarthritis

Author

Kerkhof, Hanneke J.M., primary, Lories, Rik J., additional, Meulenbelt, Ingrid, additional, Jonsdottir, Ingileif, additional, Valdes, Ana M, additional, Arp, Pascal, additional, Ingvarsson, Thorvaldur, additional, Jhamai, Mila, additional, Jonsson, Helgi, additional, Stolk, Lisette, additional, Thorleifsson, Gudmar, additional, Zhai, Guangju, additional, Zhang, Feng, additional, Zhu, Yanyan, additional, van der Breggen, Ruud, additional, Carr, Andrew, additional, Doherty, Michael, additional, Doherty, Sally, additional, Felson, David T., additional, Gonzalez, Antonio, additional, Halldorsson, Bjarni V., additional, Hart, Deborah J., additional, Hauksson, Valdimar B., additional, Hofman, Albert, additional, Ioannidis, John P.A., additional, Kloppenburg, Margreet, additional, Lane, Nancy E., additional, Loughlin, John, additional, Luyten, Frank P., additional, Nevitt, Michael C., additional, Parimi, Neeta, additional, Pols, Huibert A.P., additional, van de Putte, Tom, additional, Rivadeneira, Fernando, additional, Slagboom, Eline P., additional, Styrkársdóttir, Unnur, additional, Tsezou, Aspasia, additional, Zmuda, Joseph, additional, Spector, Tim D., additional, Stefansson, Kari, additional, Uitterlinden, André G., additional, and van Meurs, Joyce B.J., additional

Published
2010
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15. Large-scale analysis of association betweenGDF5andFRZBvariants and osteoarthritis of the hip, knee, and hand

Author

Evangelou, Evangelos, primary, Chapman, Kay, additional, Meulenbelt, Ingrid, additional, Karassa, Fotini B., additional, Loughlin, John, additional, Carr, Andrew, additional, Doherty, Michael, additional, Doherty, Sally, additional, Gómez-Reino, Juan J., additional, Gonzalez, Antonio, additional, Halldorsson, Bjarni V., additional, Hauksson, Valdimar B., additional, Hofman, Albert, additional, Hart, Deborah J., additional, Ikegawa, Shiro, additional, Ingvarsson, Thorvaldur, additional, Jiang, Qing, additional, Jonsdottir, Ingileif, additional, Jonsson, Helgi, additional, Kerkhof, Hanneke J. M., additional, Kloppenburg, Margreet, additional, Lane, Nancy E., additional, Li, Jia, additional, Lories, Rik J., additional, van Meurs, Joyce B. J., additional, Näkki, Annu, additional, Nevitt, Michael C., additional, Rodriguez-Lopez, Julio, additional, Shi, Dongquan, additional, Slagboom, P. Eline, additional, Stefansson, Kari, additional, Tsezou, Aspasia, additional, Wallis, Gillian A., additional, Watson, Christopher M., additional, Spector, Tim D., additional, Uitterlinden, Andre G., additional, Valdes, Ana M., additional, and Ioannidis, John P. A., additional

Published
2009
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27. Reply

Author

Loughlin, John, primary, Chapman, Kay, additional, and Carr, Andrew, additional

Published
2003
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31. High capacity screening of pooled compounds: Identification of the active compound without re-assay of pool members

Author

Devlin, James J., primary, Liang, Amy, additional, Trinh, Lan, additional, Polokoff, Mark A., additional, Senator, David, additional, Zheng, Wei, additional, Kondracki, Jason, additional, Kretschmer, Peter J., additional, Morser, John, additional, Lipson, Samuel E., additional, Spann, Richard, additional, Loughlin, John A., additional, Dunn, Kathryn V., additional, and Morrissey, Michael M., additional

Published
1996
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33. Multi-Tissue Epigenetic and Gene Expression Analysis Combined With Epigenome Modulation Identifies RWDD2B as a Target of Osteoarthritis Susceptibility.

Author

Parker E, Hofer IMJ, Rice SJ, Earl L, Anjum SA, Deehan DJ, and Loughlin J

Subjects
Adult, Aged, Aged, 80 and over, CRISPR-Cas Systems, Chondrocytes, CpG Islands, DNA Methylation, Female, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Osteoarthritis metabolism, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Cartilage, Articular metabolism, Epigenesis, Genetic, Osteoarthritis genetics, Synovial Membrane metabolism
Abstract

Objective: Osteoarthritis (OA) is polygenic, with more than 90 risk loci currently mapped, including at the single-nucleotide polymorphism rs6516886. Previous analysis of OA cartilage DNA identified 6 CpG dinucleotides whose methylation levels correlated with the rs6516886 genotype, forming methylation quantitative trait loci (mQTLs). We undertook this study to investigate these mQTLs and to map expression quantitative trait loci (eQTLs) across joint tissues in order to prioritize a particular gene as a target of the rs6516886 association effect., Methods: Nucleic acids were extracted from the cartilage, fat pad, synovium, and peripheral blood from OA patients. Methylation of CpGs and allelic expression imbalance of potential target genes were assessed by pyrosequencing. A chondrocyte cell line expressing deactivated Cas9 (dCas9)-TET1 was used to directly alter CpG methylation levels, with effects on gene expression quantified by polymerase chain reaction., Results: Multiple mQTLs were detected, with effects strongest in joint tissues and with methylation at CpG cg20220242 correlating most significantly with the rs6516886 genotype. CpG cg20220242 is located upstream of RWDD2B. Significant rs6516886 eQTLs were observed for this gene, with the OA risk-conferring allele of rs6516886 correlating with reduced expression CpG methylation also correlated with allelic expression of RWDD2B, forming methylation-expression QTLs (meQTLs). Deactivated Cas9-TET1 reduction in the methylation of cg20220242 increased expression of RWDD2B., Conclusion: The rs6516886 association signal is a multi-tissue meQTL involving cg20220242 and acting on RWDD2B. Modulating CpG methylation reverses the impact of the risk allele. RWDD2B codes for a protein about which little is currently known. Its further analysis as a target of OA genetic risk will provide novel insight into this complex disease., (© 2020 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Published
2021
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34. Prioritization of PLEC and GRINA as Osteoarthritis Risk Genes Through the Identification and Characterization of Novel Methylation Quantitative Trait Loci.

Author

Rice SJ, Tselepi M, Sorial AK, Aubourg G, Shepherd C, Almarza D, Skelton AJ, Pangou I, Deehan D, Reynard LN, and Loughlin J

Subjects
Adult, Aged, Alleles, Biomechanical Phenomena genetics, Cartilage, Articular metabolism, CpG Islands genetics, Female, Genetic Predisposition to Disease genetics, Genome-Wide Association Study, Genotype, Humans, Male, Membrane Proteins genetics, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors, DNA Methylation genetics, Osteoarthritis genetics, Plectin genetics, Quantitative Trait Loci genetics, Receptors, N-Methyl-D-Aspartate genetics
Abstract

Objective: To identify methylation quantitative trait loci (mQTLs) correlating with osteoarthritis (OA) risk alleles and to undertake mechanistic characterization as a means of target gene prioritization., Methods: We used genome-wide genotyping and cartilage DNA methylation array data in a discovery screen of novel OA risk loci. This was followed by methylation, gene expression analysis, and genotyping studies in additional cartilage samples, accompanied by in silico analyses., Results: We identified 4 novel OA mQTLs. The most significant mQTL contained 9 CpG sites where methylation correlated with OA risk genotype, with 5 of the CpG sites having P values <1 × 10 -10 . The 9 CpG sites reside in an interval of only 7.7 kb within the PLEC gene and form 2 distinct clusters. We were able to prioritize PLEC and the adjacent gene GRINA as independent targets of the OA risk. We identified PLEC and GRINA expression QTLs operating in cartilage, as well as methylation-expression QTLs operating on the 2 genes. GRINA and PLEC also demonstrated differential expression between OA hip and non-OA hip cartilage., Conclusion: PLEC encodes plectin, a cytoskeletal protein that maintains tissue integrity by regulating intracellular signaling in response to mechanical stimuli. GRINA encodes the ionotropic glutamate receptor TMBIM3 (transmembrane BAX inhibitor 1 motif-containing protein family member 3), which regulates cell survival. Based on our results, we hypothesize that in a joint predisposed to OA, expression of these genes alters in order to combat aberrant biomechanics, and that this is epigenetically regulated. However, carriage of the OA risk-conferring allele at this locus hinders this response and contributes to disease development., (© 2019 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)

Published
2019
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35. Correlation of the osteoarthritis susceptibility variants that map to chromosome 20q13 with an expression quantitative trait locus operating on NCOA3 and with functional variation at the polymorphism rs116855380.

Author

Gee F, Rushton MD, Loughlin J, and Reynard LN

Subjects
Alleles, Cartilage, Articular metabolism, Collagen Type II genetics, Collagen Type II metabolism, Core Binding Factor Alpha 1 Subunit genetics, Core Binding Factor Alpha 1 Subunit metabolism, Gene Expression Regulation, Genotype, Humans, Matrix Metalloproteinase 13 genetics, Matrix Metalloproteinase 13 metabolism, Nuclear Receptor Coactivator 3 metabolism, Osteoarthritis metabolism, Transcription, Genetic, Chromosomes, Human, Pair 20, Genetic Predisposition to Disease, Nuclear Receptor Coactivator 3 genetics, Osteoarthritis genetics, Polymorphism, Single Nucleotide, Quantitative Trait Loci
Abstract

Objective: To functionally characterize the osteoarthritis (OA) susceptibility variants that map to a region of high linkage disequilibrium (LD) on chromosome 20q13 marked by the single-nucleotide polymorphism (SNP) rs6094710 and encompassing NCOA3 and SULF2., Methods: Nucleic acids were extracted from the cartilage of OA patients. Overall and allelic expression of NCOA3 and SULF2 were measured by quantitative reverse transcription-polymerase chain reaction and pyrosequencing, respectively. The functional effect of SNPs within the 20q13 locus was assessed in vitro using luciferase reporter constructs and electrophoretic mobility shift assays (EMSAs). The in vivo effect of nuclear receptor coactivator 3 (NCOA3) protein depletion on primary human OA articular cartilage chondrocytes was assessed using RNA interference., Results: Expression of NCOA3 correlated with the genotype at rs6094710 (P = 0.006), and the gene demonstrated allelic expression imbalance (AEI) in individuals heterozygous for the SNP (mean AEI 1.21; P < 0.0001). In both instances, expression of the OA-associated allele was reduced. In addition, there was reduced enhancer activity of the OA-associated allele of rs116855380, a SNP in perfect LD with rs6094710 in luciferase assays (P < 0.001). EMSAs demonstrated a protein complex binding with reduced affinity to this allele. Depletion of NCOA3 led to significant changes (all P < 0.05) in the expression of genes involved in cartilage homeostasis., Conclusion: NCOA3 is subject to a cis-acting expression quantitative trait locus in articular cartilage, which correlates with the OA association signal and with the OA-associated allele of the functional SNP rs116855380, a SNP that is located only 10.3 kb upstream of NCOA3. These findings elucidate the effect of the association of the 20q13 region on OA cartilage and provide compelling evidence of a potentially causal candidate SNP., (© 2015 The Authors. Arthritis & Rheumatology is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.)

Published
2015
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36. Assessment of osteoarthritis candidate genes in a meta-analysis of nine genome-wide association studies.

Author

Rodriguez-Fontenla C, Calaza M, Evangelou E, Valdes AM, Arden N, Blanco FJ, Carr A, Chapman K, Deloukas P, Doherty M, Esko T, Garcés Aletá CM, Gomez-Reino Carnota JJ, Helgadottir H, Hofman A, Jonsdottir I, Kerkhof HJ, Kloppenburg M, McCaskie A, Ntzani EE, Ollier WE, Oreiro N, Panoutsopoulou K, Ralston SH, Ramos YF, Riancho JA, Rivadeneira F, Slagboom PE, Styrkarsdottir U, Thorsteinsdottir U, Thorleifsson G, Tsezou A, Uitterlinden AG, Wallis GA, Wilkinson JM, Zhai G, Zhu Y, Felson DT, Ioannidis JP, Loughlin J, Metspalu A, Meulenbelt I, Stefansson K, van Meurs JB, Zeggini E, Spector TD, and Gonzalez A

Subjects
Collagen Type XI genetics, Gene Frequency, Genome-Wide Association Study, Genotype, Humans, Vascular Endothelial Growth Factor A genetics, Genetic Predisposition to Disease, Osteoarthritis, Hip genetics, Osteoarthritis, Knee genetics, Polymorphism, Single Nucleotide
Abstract

Objective: To assess candidate genes for association with osteoarthritis (OA) and identify promising genetic factors and, secondarily, to assess the candidate gene approach in OA., Methods: A total of 199 candidate genes for association with OA were identified using Human Genome Epidemiology (HuGE) Navigator. All of their single-nucleotide polymorphisms (SNPs) with an allele frequency of >5% were assessed by fixed-effects meta-analysis of 9 genome-wide association studies (GWAS) that included 5,636 patients with knee OA and 16,972 control subjects and 4,349 patients with hip OA and 17,836 control subjects of European ancestry. An additional 5,921 individuals were genotyped for significantly associated SNPs in the meta-analysis. After correction for the number of independent tests, P values less than 1.58 × 10(-5) were considered significant., Results: SNPs at only 2 of the 199 candidate genes (COL11A1 and VEGF) were associated with OA in the meta-analysis. Two SNPs in COL11A1 showed association with hip OA in the combined analysis: rs4907986 (P = 1.29 × 10(-5) , odds ratio [OR] 1.12, 95% confidence interval [95% CI] 1.06-1.17) and rs1241164 (P = 1.47 × 10(-5) , OR 0.82, 95% CI 0.74-0.89). The sex-stratified analysis also showed association of COL11A1 SNP rs4908291 in women (P = 1.29 × 10(-5) , OR 0.87, 95% CI 0.82-0.92); this SNP showed linkage disequilibrium with rs4907986. A single SNP of VEGF, rs833058, showed association with hip OA in men (P = 1.35 × 10(-5) , OR 0.85, 95% CI 0.79-0.91). After additional samples were genotyped, association at one of the COL11A1 signals was reinforced, whereas association at VEGF was slightly weakened., Conclusion: Two candidate genes, COL11A1 and VEGF, were significantly associated with OA in this focused meta-analysis. The remaining candidate genes were not associated., (Copyright © 2014 by the American College of Rheumatology.)

Published
2014
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