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1.  A genome-wide association study of anorexia nervosa 
Boraska, Vesna | Franklin, Christopher S | Floyd, James AB | Thornton, Laura M | Huckins, Laura M | Southam, Lorraine | Rayner, N William | Tachmazidou, Ioanna | Klump, Kelly L | Treasure, Janet | Lewis, Cathryn M | Schmidt, Ulrike | Tozzi, Federica | Kiezebrink, Kirsty | Hebebrand, Johannes | Gorwood, Philip | Adan, Roger AH | Kas, Martien JH | Favaro, Angela | Santonastaso, Paolo | Fernández-Aranda, Fernando | Gratacos, Monica | Rybakowski, Filip | Dmitrzak-Weglarz, Monika | Kaprio, Jaakko | Keski-Rahkonen, Anna | Raevuori, Anu | Van Furth, Eric F | Landt, Margarita CT Slof-Op t | Hudson, James I | Reichborn-Kjennerud, Ted | Knudsen, Gun Peggy S | Monteleone, Palmiero | Kaplan, Allan S | Karwautz, Andreas | Hakonarson, Hakon | Berrettini, Wade H | Guo, Yiran | Li, Dong | Schork, Nicholas J. | Komaki, Gen | Ando, Tetsuya | Inoko, Hidetoshi | Esko, Tõnu | Fischer, Krista | Männik, Katrin | Metspalu, Andres | Baker, Jessica H | Cone, Roger D | Dackor, Jennifer | DeSocio, Janiece E | Hilliard, Christopher E | O'Toole, Julie K | Pantel, Jacques | Szatkiewicz, Jin P | Taico, Chrysecolla | Zerwas, Stephanie | Trace, Sara E | Davis, Oliver SP | Helder, Sietske | Bühren, Katharina | Burghardt, Roland | de Zwaan, Martina | Egberts, Karin | Ehrlich, Stefan | Herpertz-Dahlmann, Beate | Herzog, Wolfgang | Imgart, Hartmut | Scherag, André | Scherag, Susann | Zipfel, Stephan | Boni, Claudette | Ramoz, Nicolas | Versini, Audrey | Brandys, Marek K | Danner, Unna N | de Kovel, Carolien | Hendriks, Judith | Koeleman, Bobby PC | Ophoff, Roel A | Strengman, Eric | van Elburg, Annemarie A | Bruson, Alice | Clementi, Maurizio | Degortes, Daniela | Forzan, Monica | Tenconi, Elena | Docampo, Elisa | Escaramís, Geòrgia | Jiménez-Murcia, Susana | Lissowska, Jolanta | Rajewski, Andrzej | Szeszenia-Dabrowska, Neonila | Slopien, Agnieszka | Hauser, Joanna | Karhunen, Leila | Meulenbelt, Ingrid | Slagboom, P Eline | Tortorella, Alfonso | Maj, Mario | Dedoussis, George | Dikeos, Dimitris | Gonidakis, Fragiskos | Tziouvas, Konstantinos | Tsitsika, Artemis | Papezova, Hana | Slachtova, Lenka | Martaskova, Debora | Kennedy, James L. | Levitan, Robert D. | Yilmaz, Zeynep | Huemer, Julia | Koubek, Doris | Merl, Elisabeth | Wagner, Gudrun | Lichtenstein, Paul | Breen, Gerome | Cohen-Woods, Sarah | Farmer, Anne | McGuffin, Peter | Cichon, Sven | Giegling, Ina | Herms, Stefan | Rujescu, Dan | Schreiber, Stefan | Wichmann, H-Erich | Dina, Christian | Sladek, Rob | Gambaro, Giovanni | Soranzo, Nicole | Julia, Antonio | Marsal, Sara | Rabionet, Raquel | Gaborieau, Valerie | Dick, Danielle M | Palotie, Aarno | Ripatti, Samuli | Widén, Elisabeth | Andreassen, Ole A | Espeseth, Thomas | Lundervold, Astri | Reinvang, Ivar | Steen, Vidar M | Le Hellard, Stephanie | Mattingsdal, Morten | Ntalla, Ioanna | Bencko, Vladimir | Foretova, Lenka | Janout, Vladimir | Navratilova, Marie | Gallinger, Steven | Pinto, Dalila | Scherer, Stephen | Aschauer, Harald | Carlberg, Laura | Schosser, Alexandra | Alfredsson, Lars | Ding, Bo | Klareskog, Lars | Padyukov, Leonid | Finan, Chris | Kalsi, Gursharan | Roberts, Marion | Logan, Darren W | Peltonen, Leena | Ritchie, Graham RS | Barrett, Jeffrey C | Estivill, Xavier | Hinney, Anke | Sullivan, Patrick F | Collier, David A | Zeggini, Eleftheria | Bulik, Cynthia M
Molecular psychiatry  2014;19(10):1085-1094.
Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2,907 cases with AN from 14 countries (15 sites) and 14,860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery datasets. Seventy-six (72 independent) SNPs were taken forward for in silico (two datasets) or de novo (13 datasets) replication genotyping in 2,677 independent AN cases and 8,629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication datasets comprised 5,551 AN cases and 21,080 controls. AN subtype analyses (1,606 AN restricting; 1,445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01×10-7) in SOX2OT and rs17030795 (P=5.84×10-6) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76×10-6) between CUL3 and FAM124B and rs1886797 (P=8.05×10-6) near SPATA13. Comparing discovery to replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4×10-6), strongly suggesting that true findings exist but that our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field.
doi:10.1038/mp.2013.187
PMCID: PMC4325090  PMID: 24514567
anorexia nervosa; eating disorders; GWAS; genome-wide association study; body mass index; metabolic
2.  Genes Involved in the Osteoarthritis Process Identified through Genome Wide Expression Analysis in Articular Cartilage; the RAAK Study 
PLoS ONE  2014;9(7):e103056.
Objective
Identify gene expression profiles associated with OA processes in articular cartilage and determine pathways changing during the disease process.
Methods
Genome wide gene expression was determined in paired samples of OA affected and preserved cartilage of the same joint using microarray analysis for 33 patients of the RAAK study. Results were replicated in independent samples by RT-qPCR and immunohistochemistry. Profiles were analyzed with the online analysis tools DAVID and STRING to identify enrichment for specific pathways and protein-protein interactions.
Results
Among the 1717 genes that were significantly differently expressed between OA affected and preserved cartilage we found significant enrichment for genes involved in skeletal development (e.g. TNFRSF11B and FRZB). Also several inflammatory genes such as CD55, PTGES and TNFAIP6, previously identified in within-joint analyses as well as in analyses comparing preserved cartilage from OA affected joints versus healthy cartilage were among the top genes. Of note was the high up-regulation of NGF in OA cartilage. RT-qPCR confirmed differential expression for 18 out of 19 genes with expression changes of 2-fold or higher, and immunohistochemistry of selected genes showed a concordant change in protein expression. Most of these changes associated with OA severity (Mankin score) but were independent of joint-site or sex.
Conclusion
We provide further insights into the ongoing OA pathophysiological processes in cartilage, in particular into differences in macroscopically intact cartilage compared to OA affected cartilage, which seem relatively consistent and independent of sex or joint. We advocate that development of treatment could benefit by focusing on these similarities in gene expression changes and/or pathways.
doi:10.1371/journal.pone.0103056
PMCID: PMC4108379  PMID: 25054223
3.  A genome-wide association study of anorexia nervosa 
Boraska, Vesna | Franklin, Christopher S | Floyd, James AB | Thornton, Laura M | Huckins, Laura M | Southam, Lorraine | Rayner, N William | Tachmazidou, Ioanna | Klump, Kelly L | Treasure, Janet | Lewis, Cathryn M | Schmidt, Ulrike | Tozzi, Federica | Kiezebrink, Kirsty | Hebebrand, Johannes | Gorwood, Philip | Adan, Roger AH | Kas, Martien JH | Favaro, Angela | Santonastaso, Paolo | Fernández-Aranda, Fernando | Gratacos, Monica | Rybakowski, Filip | Dmitrzak-Weglarz, Monika | Kaprio, Jaakko | Keski-Rahkonen, Anna | Raevuori, Anu | Van Furth, Eric F | Slof-Op t Landt, Margarita CT | Hudson, James I | Reichborn-Kjennerud, Ted | Knudsen, Gun Peggy S | Monteleone, Palmiero | Kaplan, Allan S | Karwautz, Andreas | Hakonarson, Hakon | Berrettini, Wade H | Guo, Yiran | Li, Dong | Schork, Nicholas J. | Komaki, Gen | Ando, Tetsuya | Inoko, Hidetoshi | Esko, Tõnu | Fischer, Krista | Männik, Katrin | Metspalu, Andres | Baker, Jessica H | Cone, Roger D | Dackor, Jennifer | DeSocio, Janiece E | Hilliard, Christopher E | O’Toole, Julie K | Pantel, Jacques | Szatkiewicz, Jin P | Taico, Chrysecolla | Zerwas, Stephanie | Trace, Sara E | Davis, Oliver SP | Helder, Sietske | Bühren, Katharina | Burghardt, Roland | de Zwaan, Martina | Egberts, Karin | Ehrlich, Stefan | Herpertz-Dahlmann, Beate | Herzog, Wolfgang | Imgart, Hartmut | Scherag, André | Scherag, Susann | Zipfel, Stephan | Boni, Claudette | Ramoz, Nicolas | Versini, Audrey | Brandys, Marek K | Danner, Unna N | de Kovel, Carolien | Hendriks, Judith | Koeleman, Bobby PC | Ophoff, Roel A | Strengman, Eric | van Elburg, Annemarie A | Bruson, Alice | Clementi, Maurizio | Degortes, Daniela | Forzan, Monica | Tenconi, Elena | Docampo, Elisa | Escaramís, Geòrgia | Jiménez-Murcia, Susana | Lissowska, Jolanta | Rajewski, Andrzej | Szeszenia-Dabrowska, Neonila | Slopien, Agnieszka | Hauser, Joanna | Karhunen, Leila | Meulenbelt, Ingrid | Slagboom, P Eline | Tortorella, Alfonso | Maj, Mario | Dedoussis, George | Dikeos, Dimitris | Gonidakis, Fragiskos | Tziouvas, Konstantinos | Tsitsika, Artemis | Papezova, Hana | Slachtova, Lenka | Martaskova, Debora | Kennedy, James L. | Levitan, Robert D. | Yilmaz, Zeynep | Huemer, Julia | Koubek, Doris | Merl, Elisabeth | Wagner, Gudrun | Lichtenstein, Paul | Breen, Gerome | Cohen-Woods, Sarah | Farmer, Anne | McGuffin, Peter | Cichon, Sven | Giegling, Ina | Herms, Stefan | Rujescu, Dan | Schreiber, Stefan | Wichmann, H-Erich | Dina, Christian | Sladek, Rob | Gambaro, Giovanni | Soranzo, Nicole | Julia, Antonio | Marsal, Sara | Rabionet, Raquel | Gaborieau, Valerie | Dick, Danielle M | Palotie, Aarno | Ripatti, Samuli | Widén, Elisabeth | Andreassen, Ole A | Espeseth, Thomas | Lundervold, Astri | Reinvang, Ivar | Steen, Vidar M | Le Hellard, Stephanie | Mattingsdal, Morten | Ntalla, Ioanna | Bencko, Vladimir | Foretova, Lenka | Janout, Vladimir | Navratilova, Marie | Gallinger, Steven | Pinto, Dalila | Scherer, Stephen | Aschauer, Harald | Carlberg, Laura | Schosser, Alexandra | Alfredsson, Lars | Ding, Bo | Klareskog, Lars | Padyukov, Leonid | Finan, Chris | Kalsi, Gursharan | Roberts, Marion | Logan, Darren W | Peltonen, Leena | Ritchie, Graham RS | Barrett, Jeffrey C | Estivill, Xavier | Hinney, Anke | Sullivan, Patrick F | Collier, David A | Zeggini, Eleftheria | Bulik, Cynthia M
Molecular psychiatry  2010;16(9):10.1038/mp.2010.107.
Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2,907 cases with AN from 14 countries (15 sites) and 14,860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery datasets. Seventy-six (72 independent) SNPs were taken forward for in silico (two datasets) or de novo (13 datasets) replication genotyping in 2,677 independent AN cases and 8,629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication datasets comprised 5,551 AN cases and 21,080 controls. AN subtype analyses (1,606 AN restricting; 1,445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01×10−7) in SOX2OT and rs17030795 (P=5.84×10−6) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76×10−6) between CUL3 and FAM124B and rs1886797 (P=8.05×10−6) near SPATA13. Comparing discovery to replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P= 4×10−6), strongly suggesting that true findings exist but that our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field.
doi:10.1038/mp.2010.107
PMCID: PMC3859494  PMID: 21079607
anorexia nervosa; eating disorders; GWAS; genome-wide association study; body mass index; metabolic
4.  Hip Ontogenesis: How Evolution, Genes, and Load History Shape Hip Morphotype and Cartilotype 
Background
Developmental hip disorders (DHDs), eg, developmental dysplasia of the hip, slipped capitis femoris epiphysis, and femoroacetabular impingement, can be considered morphology variants of the normal hip. The femoroacetabular morphology of DHD is believed to induce osteoarthritis (OA) through local cumulative mechanical overload acting on genetically controlled patterning systems and subsequent damage of joint structures. However, it is unclear why hip morphology differs between individuals with seemingly comparable load histories and why certain hips with DHD progress to symptomatic OA whereas others do not.
Questions/Purposes
We asked (1) which mechanical factors influence growth and development of the proximal femur; and (2) which genes or genetic mechanisms are associated with hip ontogenesis.
Methods
We performed a systematic literature review of mechanical and genetic factors of hip ontogeny. We focused on three fields that in recent years have advanced our knowledge of adult hip morphology: imaging, evolution, and genetics.
Where Are We Now?
Mechanical factors can be understood in view of human evolutionary peculiarities and may summate to load histories conducive to DHD. Genetic factors most likely act through multiple genes, each with modest effect sizes. Single genes that explain a DHD are therefore unlikely to be found. Apparently, the interplay between genes and load history not only determines hip morphotype, but also joint cartilage robustness (“cartilotype”) and resistance to symptomatic OA.
Where Do We Need to Go?
We need therapies that can improve both morphotype and cartilotype.
How Do We Get There?
Better phenotyping, improving classification systems of hip morphology, and comparative population studies can be done with existing methods. Quantifying load histories likely requires new tools, but proof of principle of modifying morphotype in treatment of DDH and of cartilotype with exercise is available.
doi:10.1007/s11999-012-2511-4
PMCID: PMC3492609  PMID: 22926490
5.  GREM1, FRZB and DKK1 mRNA levels correlate with osteoarthritis and are regulated by osteoarthritis-associated factors 
Arthritis Research & Therapy  2013;15(5):R126.
Introduction
Osteoarthritis is, at least in a subset of patients, associated with hypertrophic differentiation of articular chondrocytes. Recently, we identified the bone morphogenetic protein (BMP) and wingless-type MMTV integration site (WNT) signaling antagonists Gremlin 1 (GREM1), frizzled-related protein (FRZB) and dickkopf 1 homolog (Xenopus laevis) (DKK1) as articular cartilage’s natural brakes of hypertrophic differentiation. In this study, we investigated whether factors implicated in osteoarthritis or regulation of chondrocyte hypertrophy influence GREM1, FRZB and DKK1 expression levels.
Methods
GREM1, FRZB and DKK1 mRNA levels were studied in articular cartilage from healthy preadolescents and healthy adults as well as in preserved and degrading osteoarthritic cartilage from the same osteoarthritic joint by quantitative PCR. Subsequently, we exposed human articular chondrocytes to WNT, BMP, IL-1β, Indian hedgehog, parathyroid hormone-related peptide, mechanical loading, different medium tonicities or distinct oxygen levels and investigated GREM1, FRZB and DKK1 expression levels using a time-course analysis.
Results
GREM1, FRZB and DKK1 mRNA expression were strongly decreased in osteoarthritis. Moreover, this downregulation is stronger in degrading cartilage compared with macroscopically preserved cartilage from the same osteoarthritic joint. WNT, BMP, IL-1β signaling and mechanical loading regulated GREM1, FRZB and DKK1 mRNA levels. Indian hedgehog, parathyroid hormone-related peptide and tonicity influenced the mRNA levels of at least one antagonist, while oxygen levels did not demonstrate any statistically significant effect. Interestingly, BMP and WNT signaling upregulated the expression of each other’s antagonists.
Conclusions
Together, the current study demonstrates an inverse correlation between osteoarthritis and GREM1, FRZB and DKK1 gene expression in cartilage and provides insight into the underlying transcriptional regulation. Furthermore, we show that BMP and WNT signaling are linked in a negative feedback loop, which might prove essential in articular cartilage homeostasis by balancing BMP and WNT activity.
doi:10.1186/ar4306
PMCID: PMC3978825  PMID: 24286177
6.  Genome-wide association study meta-analysis of chronic widespread pain: evidence for involvement of the 5p15.2 region 
Annals of the rheumatic diseases  2012;72(3):427-436.
Objectives
Chronic widespread pain (CWP) is a common disorder affecting ~10% of the general population and has an estimated heritability of 48-52%. In the first large-scale genome-wide association study (GWAS) meta-analysis, we aimed to identify common genetic variants associated with CWP.
Methods
We conducted a GWAS meta-analysis in 1,308 female CWP cases and 5,791 controls of European descent, and replicated the effects of the genetic variants with suggestive evidence for association in 1,480 CWP cases and 7,989 controls (P<1×10−5). Subsequently, we studied gene expression levels of the nearest genes in two chronic inflammatory pain mouse models, and examined 92 genetic variants previously described associated with pain.
Results
The minor C-allele of rs13361160 on chromosome 5p15.2, located upstream of CCT5 and downstream of FAM173B, was found to be associated with a 30% higher risk of CWP (MAF=43%; OR=1.30, 95%CI=1.19-1.42, P=1.2×10−8). Combined with the replication, we observed a slightly attenuated OR of 1.17 (95%CI=1.10-1.24, P=4.7×10−7) with moderate heterogeneity (I2=28.4%). However, in a sensitivity analysis that only allowed studies with joint-specific pain, the combined association was genome-wide significant (OR=1.23, 95%CI=1.14-1.32, P=3.4×10−8, I2=0%). Expression levels of Cct5 and Fam173b in mice with inflammatory pain were higher in the lumbar spinal cord, not in the lumbar dorsal root ganglions, compared to mice without pain. None of the 92 genetic variants previously described were significantly associated with pain (P>7.7×10−4).
Conclusions
We identified a common genetic variant on chromosome 5p15.2 associated with joint-specific CWP in humans. This work suggests that CCT5 and FAM173B are promising targets in the regulation of pain.
doi:10.1136/annrheumdis-2012-201742
PMCID: PMC3691951  PMID: 22956598
Gene Polymorphism; Fibromyalgia/Pain Syndromes; Epidemiology
7.  Identification and systematic annotation of tissue-specific differentially methylated regions using the Illumina 450k array 
Background
DNA methylation has been recognized as a key mechanism in cell differentiation. Various studies have compared tissues to characterize epigenetically regulated genomic regions, but due to differences in study design and focus there still is no consensus as to the annotation of genomic regions predominantly involved in tissue-specific methylation. We used a new algorithm to identify and annotate tissue-specific differentially methylated regions (tDMRs) from Illumina 450k chip data for four peripheral tissues (blood, saliva, buccal swabs and hair follicles) and six internal tissues (liver, muscle, pancreas, subcutaneous fat, omentum and spleen with matched blood samples).
Results
The majority of tDMRs, in both relative and absolute terms, occurred in CpG-poor regions. Further analysis revealed that these regions were associated with alternative transcription events (alternative first exons, mutually exclusive exons and cassette exons). Only a minority of tDMRs mapped to gene-body CpG islands (13%) or CpG islands shores (25%) suggesting a less prominent role for these regions than indicated previously. Implementation of ENCODE annotations showed enrichment of tDMRs in DNase hypersensitive sites and transcription factor binding sites. Despite the predominance of tissue differences, inter-individual differences in DNA methylation in internal tissues were correlated with those for blood for a subset of CpG sites in a locus- and tissue-specific manner.
Conclusions
We conclude that tDMRs preferentially occur in CpG-poor regions and are associated with alternative transcription. Furthermore, our data suggest the utility of creating an atlas cataloguing variably methylated regions in internal tissues that correlate to DNA methylation measured in easy accessible peripheral tissues.
doi:10.1186/1756-8935-6-26
PMCID: PMC3750594  PMID: 23919675
Differentially methylated region; Illumina 450k; Annotation; Algorithm; Tissue
8.  Meta-analysis of genome-wide association studies confirms a susceptibility locus for knee osteoarthritis on chromosome 7q22 
Evangelou, Evangelos | Valdes, Ana M. | Kerkhof, Hanneke J.M | Styrkarsdottir, Unnur | Zhu, YanYan | Meulenbelt, Ingrid | Lories, Rik J. | Karassa, Fotini B. | Tylzanowski, Przemko | Bos, Steffan D. | Akune, Toru | Arden, Nigel K. | Carr, Andrew | Chapman, Kay | Cupples, L. Adrienne | Dai, Jin | Deloukas, Panos | Doherty, Michael | Doherty, Sally | Engstrom, Gunnar | Gonzalez, Antonio | Halldorsson, Bjarni V. | Hammond, Christina L. | Hart, Deborah J. | Helgadottir, Hafdis | Hofman, Albert | Ikegawa, Shiro | Ingvarsson, Thorvaldur | Jiang, Qing | Jonsson, Helgi | Kaprio, Jaakko | Kawaguchi, Hiroshi | Kisand, Kalle | Kloppenburg, Margreet | Kujala, Urho M. | Lohmander, L. Stefan | Loughlin, John | Luyten, Frank P. | Mabuchi, Akihiko | McCaskie, Andrew | Nakajima, Masahiro | Nilsson, Peter M. | Nishida, Nao | Ollier, William E.R. | Panoutsopoulou, Kalliope | van de Putte, Tom | Ralston, Stuart H. | Rivadeneira, Fernado | Saarela, Janna | Schulte-Merker, Stefan | Slagboom, P. Eline | Sudo, Akihiro | Tamm, Agu | Tamm, Ann | Thorleifsson, Gudmar | Thorsteinsdottir, Unnur | Tsezou, Aspasia | Wallis, Gillian A. | Wilkinson, J. Mark | Yoshimura, Noriko | Zeggini, Eleftheria | Zhai, Guangju | Zhang, Feng | Jonsdottir, Ingileif | Uitterlinden, Andre G. | Felson, David T | van Meurs, Joyce B. | Stefansson, Kari | Ioannidis, John P.A. | Spector, Timothy D.
Annals of the rheumatic diseases  2010;70(2):349-355.
Osteoarthritis (OA) is the most prevalent form of arthritis and accounts for substantial morbidity and disability, particularly in the elderly. It is characterized by changes in joint structure including degeneration of the articular cartilage and its etiology is multifactorial with a strong postulated genetic component. We performed a meta-analysis of four genome-wide association (GWA) studies of 2,371 knee OA cases and 35,909 controls in Caucasian populations. Replication of the top hits was attempted with data from additional ten replication datasets. With a cumulative sample size of 6,709 cases and 44,439 controls, we identified one genome-wide significant locus on chromosome 7q22 for knee OA (rs4730250, p-value=9.2×10−9), thereby confirming its role as a susceptibility locus for OA. The associated signal is located within a large (500kb) linkage disequilibrium (LD) block that contains six genes; PRKAR2B (protein kinase, cAMP-dependent, regulatory, type II, beta), HPB1 (HMG-box transcription factor 1), COG5 (component of oligomeric golgi complex 5), GPR22 (G protein-coupled receptor 22), DUS4L (dihydrouridine synthase 4-like), and BCAP29 (the B-cell receptor-associated protein 29). Gene expression analyses of the (six) genes in primary cells derived from different joint tissues confirmed expression of all the genes in the joint environment.
doi:10.1136/ard.2010.132787
PMCID: PMC3615180  PMID: 21068099
9.  A Meta-Analysis of Thyroid-Related Traits Reveals Novel Loci and Gender-Specific Differences in the Regulation of Thyroid Function 
Porcu, Eleonora | Medici, Marco | Pistis, Giorgio | Volpato, Claudia B. | Wilson, Scott G. | Cappola, Anne R. | Bos, Steffan D. | Deelen, Joris | den Heijer, Martin | Freathy, Rachel M. | Lahti, Jari | Liu, Chunyu | Lopez, Lorna M. | Nolte, Ilja M. | O'Connell, Jeffrey R. | Tanaka, Toshiko | Trompet, Stella | Arnold, Alice | Bandinelli, Stefania | Beekman, Marian | Böhringer, Stefan | Brown, Suzanne J. | Buckley, Brendan M. | Camaschella, Clara | de Craen, Anton J. M. | Davies, Gail | de Visser, Marieke C. H. | Ford, Ian | Forsen, Tom | Frayling, Timothy M. | Fugazzola, Laura | Gögele, Martin | Hattersley, Andrew T. | Hermus, Ad R. | Hofman, Albert | Houwing-Duistermaat, Jeanine J. | Jensen, Richard A. | Kajantie, Eero | Kloppenburg, Margreet | Lim, Ee M. | Masciullo, Corrado | Mariotti, Stefano | Minelli, Cosetta | Mitchell, Braxton D. | Nagaraja, Ramaiah | Netea-Maier, Romana T. | Palotie, Aarno | Persani, Luca | Piras, Maria G. | Psaty, Bruce M. | Räikkönen, Katri | Richards, J. Brent | Rivadeneira, Fernando | Sala, Cinzia | Sabra, Mona M. | Sattar, Naveed | Shields, Beverley M. | Soranzo, Nicole | Starr, John M. | Stott, David J. | Sweep, Fred C. G. J. | Usala, Gianluca | van der Klauw, Melanie M. | van Heemst, Diana | van Mullem, Alies | H.Vermeulen, Sita | Visser, W. Edward | Walsh, John P. | Westendorp, Rudi G. J. | Widen, Elisabeth | Zhai, Guangju | Cucca, Francesco | Deary, Ian J. | Eriksson, Johan G. | Ferrucci, Luigi | Fox, Caroline S. | Jukema, J. Wouter | Kiemeney, Lambertus A. | Pramstaller, Peter P. | Schlessinger, David | Shuldiner, Alan R. | Slagboom, Eline P. | Uitterlinden, André G. | Vaidya, Bijay | Visser, Theo J. | Wolffenbuttel, Bruce H. R. | Meulenbelt, Ingrid | Rotter, Jerome I. | Spector, Tim D. | Hicks, Andrew A. | Toniolo, Daniela | Sanna, Serena | Peeters, Robin P. | Naitza, Silvia
PLoS Genetics  2013;9(2):e1003266.
Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism.
Author Summary
Levels of thyroid hormones are tightly regulated by TSH produced in the pituitary, and even mild alterations in their concentrations are strong indicators of thyroid pathologies, which are very common worldwide. To identify common genetic variants associated with the highly heritable markers of thyroid function, TSH and FT4, we conducted a meta-analysis of genome-wide association studies in 26,420 and 17,520 individuals, respectively, of European ancestry with normal thyroid function. Our analysis identified 26 independent genetic variants regulating these traits, several of which are new, and confirmed previously detected polymorphisms affecting TSH (within the PDE8B gene and near CAPZB, MAF/LOC440389, and NR3C2) and FT4 (within DIO1) levels. Gender-specific differences in the genetic effects of several variants for TSH and FT4 levels were identified at several loci, which offer clues to understand the known sexual dimorphism in thyroid function and pathology. Of particular clinical interest, we show that TSH-associated loci contribute not only to normal variation, but also to TSH values outside reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings add to the developing landscape of the regulation of thyroid homeostasis and the consequences of genetic variation for thyroid related diseases.
doi:10.1371/journal.pgen.1003266
PMCID: PMC3567175  PMID: 23408906
10.  A Genome-Wide Association Study identifies a locus on chromosome 7q22 to influence susceptibility for osteoarthritis 
Arthritis and Rheumatism  2010;62(2):499-510.
To identify genes involved in osteoarthritis (OA), the most prevalent form of joint disease, we performed a genome-wide association study (GWAS) in which we tested 500,510 Single Nucelotide Polymorphisms (SNPs) in 1341 OA cases and 3496 Dutch Caucasian controls. SNPs associated with at least two OA-phenotypes were analysed in 14,938 OA cases and approximately 39,000 controls. The C-allele of rs3815148 on chromosome 7q22 (MAF 23%, 172 kb upstream of the GPR22 gene) was consistently associated with a 1.14-fold increased risk (95%CI: 1.09–1.19) for knee- and/or hand-OA (p=8×10−8), and also with a 30% increased risk for knee-OA progression (95%CI: 1.03–1.64, p=0.03). This SNP is in almost complete linkage disequilibrium with rs3757713 (located 68 kb upstream of GPR22) which is associated with GPR22 expression levels in lymphoblast cell lines (p=4×10−12). GPR22 encodes an G-protein coupled receptor with unkown ligand (orphan receptor). Immunohistochemistry experiments showed absence of GPR22 in normal mouse articular cartilage or synovium. However, GPR22 positive chondrocytes were found in the upper layers of the articular cartilage of mouse knee joints that were challenged by in vivo papain treatment or in the presence of interleukin-1 driven inflammation. GRP22 positive chondrocyte-like cells were also found in osteophytes in instability-induced OA. In addition, GPR22 is also present in areas of the brain involved in locomotor function. Our findings reveal a novel common variant on chromosome 7q22 to influence susceptibility for prevalence and progression of OA.
doi:10.1002/art.27184
PMCID: PMC3354739  PMID: 20112360
11.  Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits: A Multi-Ethnic Meta-Analysis of 45,891 Individuals 
Dastani, Zari | Hivert, Marie-France | Timpson, Nicholas | Perry, John R. B. | Yuan, Xin | Scott, Robert A. | Henneman, Peter | Heid, Iris M. | Kizer, Jorge R. | Lyytikäinen, Leo-Pekka | Fuchsberger, Christian | Tanaka, Toshiko | Morris, Andrew P. | Small, Kerrin | Isaacs, Aaron | Beekman, Marian | Coassin, Stefan | Lohman, Kurt | Qi, Lu | Kanoni, Stavroula | Pankow, James S. | Uh, Hae-Won | Wu, Ying | Bidulescu, Aurelian | Rasmussen-Torvik, Laura J. | Greenwood, Celia M. T. | Ladouceur, Martin | Grimsby, Jonna | Manning, Alisa K. | Liu, Ching-Ti | Kooner, Jaspal | Mooser, Vincent E. | Vollenweider, Peter | Kapur, Karen A. | Chambers, John | Wareham, Nicholas J. | Langenberg, Claudia | Frants, Rune | Willems-vanDijk, Ko | Oostra, Ben A. | Willems, Sara M. | Lamina, Claudia | Winkler, Thomas W. | Psaty, Bruce M. | Tracy, Russell P. | Brody, Jennifer | Chen, Ida | Viikari, Jorma | Kähönen, Mika | Pramstaller, Peter P. | Evans, David M. | St. Pourcain, Beate | Sattar, Naveed | Wood, Andrew R. | Bandinelli, Stefania | Carlson, Olga D. | Egan, Josephine M. | Böhringer, Stefan | van Heemst, Diana | Kedenko, Lyudmyla | Kristiansson, Kati | Nuotio, Marja-Liisa | Loo, Britt-Marie | Harris, Tamara | Garcia, Melissa | Kanaya, Alka | Haun, Margot | Klopp, Norman | Wichmann, H.-Erich | Deloukas, Panos | Katsareli, Efi | Couper, David J. | Duncan, Bruce B. | Kloppenburg, Margreet | Adair, Linda S. | Borja, Judith B. | Wilson, James G. | Musani, Solomon | Guo, Xiuqing | Johnson, Toby | Semple, Robert | Teslovich, Tanya M. | Allison, Matthew A. | Redline, Susan | Buxbaum, Sarah G. | Mohlke, Karen L. | Meulenbelt, Ingrid | Ballantyne, Christie M. | Dedoussis, George V. | Hu, Frank B. | Liu, Yongmei | Paulweber, Bernhard | Spector, Timothy D. | Slagboom, P. Eline | Ferrucci, Luigi | Jula, Antti | Perola, Markus | Raitakari, Olli | Florez, Jose C. | Salomaa, Veikko | Eriksson, Johan G. | Frayling, Timothy M. | Hicks, Andrew A. | Lehtimäki, Terho | Smith, George Davey | Siscovick, David S. | Kronenberg, Florian | van Duijn, Cornelia | Loos, Ruth J. F. | Waterworth, Dawn M. | Meigs, James B. | Dupuis, Josee | Richards, J. Brent
PLoS Genetics  2012;8(3):e1002607.
Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10−8–1.2×10−43). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10−4). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10−3, n = 22,044), increased triglycerides (p = 2.6×10−14, n = 93,440), increased waist-to-hip ratio (p = 1.8×10−5, n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10−3, n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10−13, n = 96,748) and decreased BMI (p = 1.4×10−4, n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.
Author Summary
Serum adiponectin levels are highly heritable and are inversely correlated with the risk of type 2 diabetes (T2D), coronary artery disease, stroke, and several metabolic traits. To identify common genetic variants associated with adiponectin levels and risk of T2D and metabolic traits, we conducted a meta-analysis of genome-wide association studies of 45,891 multi-ethnic individuals. In addition to confirming that variants at the ADIPOQ and CDH13 loci influence adiponectin levels, our analyses revealed that 10 new loci also affecting circulating adiponectin levels. We demonstrated that expression levels of several genes in these candidate regions are associated with serum adiponectin levels. Using a powerful novel method to assess the contribution of the identified variants with other traits using summary-level results from large-scale GWAS consortia, we provide evidence that the risk alleles for adiponectin are associated with deleterious changes in T2D risk and metabolic syndrome traits (triglycerides, HDL, post-prandial glucose, insulin, and waist-to-hip ratio), demonstrating that the identified loci, taken together, impact upon metabolic disease.
doi:10.1371/journal.pgen.1002607
PMCID: PMC3315470  PMID: 22479202
12.  Recommendations for standardization and phenotype definitions in genetic studies of osteoarthritis: the TREAT-OA consortium 
Objective
To address the need for standardization of osteoarthritis (OA) phenotypes by examining the effect of heterogeneity among symptomatic (SOA) and radiographic osteoarthritis (ROA) phenotypes.
Methods
Descriptions of OA phenotypes of the 28 studies involved in the TREAT-OA consortium were collected. To investigate whether different OA definitions result in different association results, we created hip OA definitions used within the consortium in the Rotterdam Study-I and tested the association of hip OA with gender, age and BMI using one-way ANOVA. For radiographic OA, we standardized the hip, knee and hand ROA definitions and calculated prevalence's of ROA before and after standardization in 9 cohort studies. This procedure could only be performed in cohort studies and standardization of SOA definitions was not feasible at this moment.
Results
In this consortium, all studies with symptomatic OA phenotypes (knee, hip and hand) used a different definition and/or assessment of OA status. For knee, hip and hand radiographic OA 5, 4 and 7 different definitions were used, respectively. Different hip OA definitions do lead to different association results. For example, we showed in the Rotterdam Study-I that hip OA defined as “at least definite JSN and one definite osteophyte” was not associated with gender (p=0.22), but defined as “at least one definite osteophyte” was significantly associated with gender (p=3×10−9). Therefore, a standardization process was undertaken for radiographic OA definitions. Before standardization a wide range of ROA prevalence's was observed in the 9 cohorts studied. After standardization the range in prevalence of knee and hip ROA was small. Standardization of SOA phenotypes was not possible due to the case-control design of the studies.
Conclusion
Phenotype definitions influence the prevalence of OA and association with clinical variables. ROA phenotypes within the TREAT-OA consortium were standardized to reduce heterogeneity and improve power in future genetics studies.
doi:10.1016/j.joca.2010.10.027
PMCID: PMC3236091  PMID: 21059398
13.  A genome-wide linkage scan reveals CD53 as an important regulator of innate TNF-α levels 
Cytokines are major immune system regulators. Previously, innate cytokine profiles determined by lipopolysaccharide stimulation were shown to be highly heritable. To identify regulating genes in innate immunity, we analyzed data from a genome-wide linkage scan using microsatellites in osteoarthritis (OA) patients (The GARP study) and their innate cytokine data on interleukin (IL)-1β, IL-1Ra, IL-10 and tumor necrosis factor (TNF)α. A confirmation cohort consisted of the Leiden 85-Plus study. In this study, a linkage analysis was followed by manual selection of candidate genes in linkage regions showing LOD scores over 2.5. An single-nucleotide polymorphism (SNP) gene tagging method was applied to select SNPs on the basis of the highest level of gene tagging and possible functional effects. QTDT was used to identify the SNPs associated with innate cytokine production. Initial association signals were modeled by a linear mixed model. Through these analyses, we identified 10 putative genes involved in the regulation of TNFα. SNP rs6679497 in gene CD53 showed significant association with TNFα levels (P=0.001). No association of this SNP was observed with OA. A novel gene involved in the innate immune response of TNFα is identified. Genetic variation in this gene may have a role in diseases and disorders in which TNFα is closely involved.
doi:10.1038/ejhg.2010.52
PMCID: PMC2987381  PMID: 20407468
linkage; osteoarthritis; immunity; TNF; GARP; CD53
14.  Common genetic variation in the Estrogen Receptor Beta (ESR2) gene and osteoarthritis: results of a meta-analysis 
BMC Medical Genetics  2010;11:164.
Background
The objective of this study was to examine the relationship between common genetic variation of the ESR2 gene and osteoarthritis.
Methods
In the discovery study, the Rotterdam Study-I, 7 single nucleotide polymorphisms (SNPs) were genotyped and tested for association with hip (284 cases, 2772 controls), knee (665 cases, 2075 controls), and hand OA (874 cases, 2184 controls) using an additive model. In the replication stage one SNP (rs1256031) was tested in an additional 2080 hip, 1318 knee and 557 hand OA cases and 4001, 2631 and 1699 controls respectively. Fixed- and random-effects meta-analyses were performed over the complete dataset including 2364 hip, 1983 knee and 1431 hand OA cases and approximately 6000 controls.
Results
The C allele of rs1256031 was associated with a 36% increased odds of hip OA in women of the Rotterdam Study-I (OR 1.36, 95% CI 1.08-1.70, p = 0.009). Haplotype analysis and analysis of knee- and hand OA did not give additional information. With the replication studies, the meta-analysis did not show a significant effect of this SNP on hip OA in the total population (OR 1.06, 95% CI 0.99-1.15, p = 0.10). Stratification according to gender did not change the results. In this study, we had 80% power to detect an odds ratio of at least 1.14 for hip OA (α = 0.05).
Conclusion
This study showed that common genetic variation in the ESR2 gene is not likely to influence the risk of osteoarthritis with effects smaller than a 13% increase.
doi:10.1186/1471-2350-11-164
PMCID: PMC2997092  PMID: 21080949
15.  Molecular epidemiology, candidate genes versus genome-wide scans 
Genes & Nutrition  2007;2(1):27-29.
doi:10.1007/s12263-007-0002-0
PMCID: PMC2474924  PMID: 18850134
Human genetics; Disease; Genetic epidemiology; Population studies; Biomarkers; Human; Genome scans; Complex disease
16.  Novel genetic variants associated with lumbar disc degeneration in northern Europeans: a meta-analysis of 4600 subjects 
Annals of the Rheumatic Diseases  2012;72(7):1141-1148.
Objective
Lumbar disc degeneration (LDD) is an important cause of low back pain, which is a common and costly problem. LDD is characterised by disc space narrowing and osteophyte growth at the circumference of the disc. To date, the agnostic search of the genome by genome-wide association (GWA) to identify common variants associated with LDD has not been fruitful. This study is the first GWA meta-analysis of LDD.
Methods
We have developed a continuous trait based on disc space narrowing and osteophytes growth which is measurable on all forms of imaging (plain radiograph, CT scan and MRI) and performed a meta-analysis of five cohorts of Northern European extraction each having GWA data imputed to HapMap V.2.
Results
This study of 4600 individuals identified four single nucleotide polymorphisms with p<5×10−8, the threshold set for genome-wide significance. We identified a variant in the PARK2 gene (p=2.8×10−8) associated with LDD. Differential methylation at one CpG island of the PARK2 promoter was observed in a small subset of subjects (β=8.74×10−4, p=0.006).
Conclusions
LDD accounts for a considerable proportion of low back pain and the pathogenesis of LDD is poorly understood. This work provides evidence of association of the PARK2 gene and suggests that methylation of the PARK2 promoter may influence degeneration of the intervertebral disc. This gene has not previously been considered a candidate in LDD and further functional work is needed on this hitherto unsuspected pathway.
doi:10.1136/annrheumdis-2012-201551
PMCID: PMC3686263  PMID: 22993228
Gene Polymorphism; Low Back Pain; Magnetic Resonance Imaging
18.  A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip 
Annals of the Rheumatic Diseases  2013;73(12):2130-2136.
Objectives
Osteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects.
Methods
We performed a two-stage meta-analysis on more than 78 000 participants. In stage 1, we synthesised data from eight GWAS whereas data from 10 centres were used for ‘in silico’ or ‘de novo’ replication. Besides the main analysis, a stratified by sex analysis was performed to detect possible sex-specific signals. Meta-analysis was performed using inverse-variance fixed effects models. A random effects approach was also used.
Results
We accumulated 11 277 cases of radiographic and symptomatic hip OA. We prioritised eight single nucleotide polymorphism (SNPs) for follow-up in the discovery stage (4349 OA cases); five from the combined analysis, two male specific and one female specific. One locus, at 20q13, represented by rs6094710 (minor allele frequency (MAF) 4%) near the NCOA3 (nuclear receptor coactivator 3) gene, reached genome-wide significance level with p=7.9×10−9 and OR=1.28 (95% CI 1.18 to 1.39) in the combined analysis of discovery (p=5.6×10−8) and follow-up studies (p=7.3×10−4). We showed that this gene is expressed in articular cartilage and its expression was significantly reduced in OA-affected cartilage. Moreover, two loci remained suggestive associated; rs5009270 at 7q31 (MAF 30%, p=9.9×10−7, OR=1.10) and rs3757837 at 7p13 (MAF 6%, p=2.2×10−6, OR=1.27 in male specific analysis).
Conclusions
Novel genetic loci for hip OA were found in this meta-analysis of GWAS.
doi:10.1136/annrheumdis-2012-203114
PMCID: PMC4251181  PMID: 23989986
Epidemiology; Gene Polymorphism; Osteoarthritis

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