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
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
California Pacific Medical Center Research Institute, San Francisco, California, United States of America.
PLoS Genet. 2016 Oct 4;12(10):e1006260. doi: 10.1371/journal.pgen.1006260. eCollection 2016 Oct.
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.
骨关节炎是老年人中最常见且致残的疾病之一。针对骨关节炎，仅鉴定出少数基因变异，部分原因是表型异质性大。为减少异质性，我们在此研究了关节健康的结构组成部分之一——软骨厚度。我们在来自五个不同队列的13013名参与者的发现集中，对作为软骨厚度替代指标的最小关节间隙宽度（mJSW）进行了全基因组关联研究，并在来自七个独立队列的8227名个体中进行了重复验证。我们鉴定出五个全基因组显著（GWS，P≤5.0×10⁻⁸）的单核苷酸多态性（SNP），它们位于四个不同的基因座。此外，我们发现另外两个基因座得到了显著重复，但合并的荟萃分析结果略低于全基因组显著性阈值。四个新发现的相关基因座位于TGFA（rs2862851）、PIK3R1（rs10471753）、SLBP/FGFR3（rs2236995）和TREH/DDX6（rs496547）附近，而另外两个（DOT1L和SUPT3H/RUNX2）是先前已鉴定出的。我们使用多种证据对潜在的因果基因进行了系统的优先级排序。外显子组测序数据（n = 2050名个体）表明，没有罕见的外显子变异能够解释所鉴定的关联。此外，在同一受试者中，TGFA、FGFR3和PIK3R1在骨关节炎软骨病变与未病变软骨中存在差异表达。总之，我们鉴定出四个新基因座（TGFA、PIK3R1、FGFR3和TREH），并确认了两个已知与软骨厚度相关的基因座。所鉴定的关联并非由罕见的外显子变异引起。这是首次将TGFA与人类骨关节炎联系起来的报告，它可能成为未来治疗的新靶点。
