Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis

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.

[1]  L. Reynard Analysis of genetics and DNA methylation in osteoarthritis: What have we learnt about the disease? , 2017, Seminars in cell & developmental biology.

[2]  J. Vandesompele,et al.  An update on LNCipedia: a database for annotated human lncRNA sequences , 2015, Nucleic Acids Res..

[3]  Michael Q. Zhang,et al.  Integrative analysis of 111 reference human epigenomes , 2015, Nature.

[4]  J. Hirschhorn,et al.  Biological interpretation of genome-wide association studies using predicted gene functions , 2015, Nature Communications.

[5]  Lennart Martens,et al.  An update on LNCipedia: a database for annotated human lncRNA sequences , 2014, Nucleic acids research.

[6]  Ross M. Fraser,et al.  Defining the role of common variation in the genomic and biological architecture of adult human height , 2014, Nature Genetics.

[7]  H. Baba,et al.  A genome-wide association study identifies susceptibility loci for ossification of the posterior longitudinal ligament of the spine , 2014, Nature Genetics.

[8]  J. Goeman,et al.  Genes Involved in the Osteoarthritis Process Identified through Genome Wide Expression Analysis in Articular Cartilage; the RAAK Study , 2014, PloS one.

[9]  R. Andrews,et al.  Innate Immune Activity Conditions the Effect of Regulatory Variants upon Monocyte Gene Expression , 2014, Science.

[10]  Eric Boerwinkle,et al.  Genetic Determinants Influencing Human Serum Metabolome among African Americans , 2014, PLoS genetics.

[11]  M. Peters,et al.  Systematic identification of trans eQTLs as putative drivers of known disease associations , 2013, Nature Genetics.

[12]  Sahar Mansour,et al.  Mutations in PIK3R1 cause SHORT syndrome. , 2013, American journal of human genetics.

[13]  Christian Gieger,et al.  Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture , 2013, Nature Genetics.

[14]  A. Uitterlinden,et al.  The DOT1L rs12982744 polymorphism is associated with osteoarthritis of the hip with genome-wide statistical significance in males , 2013, Annals of the rheumatic diseases.

[15]  Fernando Rivadeneira,et al.  Bone parameters across different types of hip osteoarthritis and their relationship to osteoporotic fracture risk. , 2013, Arthritis and rheumatism.

[16]  Liangdan Sun,et al.  Association analyses identify three susceptibility Loci for vitiligo in the Chinese Han population. , 2013, The Journal of investigative dermatology.

[17]  Buhm Han,et al.  Chromatin marks identify critical cell types for fine mapping complex trait variants , 2012 .

[18]  David Haussler,et al.  ENCODE Data in the UCSC Genome Browser: year 5 update , 2012, Nucleic Acids Res..

[19]  W. Reardon,et al.  Mutations in PIK 3 R 1 Cause SHORT Syndrome , 2013 .

[20]  A. Uitterlinden,et al.  Osteoarthritis year 2012 in review: genetics and genomics. , 2012, Osteoarthritis and cartilage.

[21]  Shane J. Neph,et al.  Systematic Localization of Common Disease-Associated Variation in Regulatory DNA , 2012, Science.

[22]  Andres Metspalu,et al.  Identification of new susceptibility loci for osteoarthritis (arcOGEN): a genome-wide association study , 2012, The Lancet.

[23]  Gunwoo Kim,et al.  Transforming growth factor alpha controls the transition from hypertrophic cartilage to bone during endochondral bone growth. , 2012, Bone.

[24]  M. Peters,et al.  Genome-wide association and functional studies identify the DOT1L gene to be involved in cartilage thickness and hip osteoarthritis , 2012, Proceedings of the National Academy of Sciences.

[25]  Daniel L. Koller,et al.  Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture , 2012, Nature Genetics.

[26]  J. Bijlsma,et al.  Radiographic features of knee and hip osteoarthritis represent characteristics of an individual, in addition to severity of osteoarthritis , 2012, Scandinavian journal of rheumatology.

[27]  Manolis Kellis,et al.  HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants , 2011, Nucleic Acids Res..

[28]  Xihong Lin,et al.  Rare-variant association testing for sequencing data with the sequence kernel association test. , 2011, American journal of human genetics.

[29]  Soumya Raychaudhuri,et al.  VIZ-GRAIL: visualizing functional connections across disease loci , 2011, Bioinform..

[30]  Robert M. Plenge,et al.  Meta-Analysis of Genome-Wide Association Studies in Celiac Disease and Rheumatoid Arthritis Identifies Fourteen Non-HLA Shared Loci , 2011, PLoS genetics.

[31]  P. Visscher,et al.  GCTA: a tool for genome-wide complex trait analysis. , 2011, American journal of human genetics.

[32]  Simon C. Potter,et al.  Insights into the genetic architecture of osteoarthritis from stage 1 of the arcOGEN study , 2010, Annals of the rheumatic diseases.

[33]  Bjarni V. Halldórsson,et al.  Meta-analysis of genome-wide association studies confirms a susceptibility locus for knee osteoarthritis on chromosome 7q22 , 2010, Annals of the rheumatic diseases.

[34]  A. Hofman,et al.  Recommendations for standardization and phenotype definitions in genetic studies of osteoarthritis: the TREAT-OA consortium. , 2010, Osteoarthritis and cartilage.

[35]  T. Mikkelsen,et al.  The NIH Roadmap Epigenomics Mapping Consortium , 2010, Nature Biotechnology.

[36]  C. Cooper,et al.  Involvement of different risk factors in clinically severe large joint osteoarthritis according to the presence of hand interphalangeal nodes. , 2010, Arthritis and rheumatism.

[37]  Ayellet V. Segrè,et al.  Hundreds of variants clustered in genomic loci and biological pathways affect human height , 2010, Nature.

[38]  Michael Boehnke,et al.  LocusZoom: regional visualization of genome-wide association scan results , 2010, Bioinform..

[39]  Yun Li,et al.  METAL: fast and efficient meta-analysis of genomewide association scans , 2010, Bioinform..

[40]  T. Libermann,et al.  GADD45β Enhances Col10a1 Transcription via the MTK1/MKK3/6/p38 Axis and Activation of C/EBPβ-TAD4 in Terminally Differentiating Chondrocytes* , 2010, The Journal of Biological Chemistry.

[41]  Ying Wang,et al.  Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus , 2009, Nature Genetics.

[42]  Alberto Piazza,et al.  Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants , 2009, Nature Genetics.

[43]  Andrew D. Johnson,et al.  SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap , 2008, Bioinform..

[44]  T. Aigner,et al.  Transforming growth factor alpha suppression of articular chondrocyte phenotype and Sox9 expression in a rat model of osteoarthritis. , 2007, Arthritis and rheumatism.

[45]  B. Koes,et al.  Validity and reliability of three definitions of hip osteoarthritis: cross sectional and longitudinal approach , 2004, Annals of the rheumatic diseases.

[46]  M. Nevitt,et al.  Progression of radiographic hip osteoarthritis over eight years in a community sample of elderly white women. , 2004, Arthritis and rheumatism.

[47]  Tom H. Pringle,et al.  The human genome browser at UCSC. , 2002, Genome research.

[48]  L. Lohmander,et al.  Assessment of primary hip osteoarthritis: comparison of radiographic methods using colon radiographs , 2000, Annals of the rheumatic diseases.

[49]  Y. Kitamura,et al.  Cbfa1 Is a Positive Regulatory Factor in Chondrocyte Maturation* , 2000, The Journal of Biological Chemistry.

[50]  S. Cummings,et al.  Radiographic osteoarthritis of the hip and bone mineral density. The Study of Osteoporotic Fractures Research Group. , 1995, Arthritis and rheumatism.