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Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis
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نویسنده
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castaño-betancourt m.c. ,evans d.s. ,ramos y.f.m. ,boer c.g. ,metrustry s. ,liu y. ,den hollander w. ,van rooij j. ,kraus v.b. ,yau m.s. ,mitchell b.d. ,muir k. ,hofman a. ,doherty m. ,doherty s. ,zhang w. ,kraaij r. ,rivadeneira f. ,barrett-connor e. ,maciewicz r.a. ,arden n. ,nelissen r.g.h.h. ,kloppenburg m. ,jordan j.m. ,nevitt m.c. ,slagboom e.p. ,hart d.j. ,lafeber f. ,styrkarsdottir u. ,zeggini e. ,evangelou e. ,spector t.d. ,uitterlinden a.g. ,lane n.e. ,meulenbelt i. ,valdes a.m. ,van meurs j.b.j.
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منبع
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plos genetics - 2016 - دوره : 12 - شماره : 10
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چکیده
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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. © 2016 public library of science. all rights reserved.
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آدرس
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department of internal medicine,erasmus medical center,rotterdam, Netherlands, california pacific medical center research institute,san francisco,ca, United States, department of medical statistics and bioinformatics,section molecular epidemiology,leiden university medical center,leiden, Netherlands, department of internal medicine,erasmus medical center,rotterdam, Netherlands, department of twins research and genetic epidemiology unit,king’s college london,london, United Kingdom, thurston arthritis research center,university of north carolina,chapel hill,nc, United States, department of medical statistics and bioinformatics,section molecular epidemiology,leiden university medical center,leiden, Netherlands, department of internal medicine,erasmus medical center,rotterdam, Netherlands, duke molecular physiology institute and division of rheumatology,duke university school of medicine,durham,nc, United States, departments of medicine and epidemiology & public health,university of maryland school of medicine,baltimore,md, United States, departments of medicine and epidemiology & public health,university of maryland school of medicine,baltimore,md,united states,geriatrics research and education clinical center,baltimore veterans administration medical center,baltimore,md, United States, health sciences research institute,university of warwick,warwick, United Kingdom, department of epidemiology,erasmus medical center,rotterdam,netherlands,department of epidemiology,harvard t.h. school of public health,boston,ma, United States, school of medicine,university of nottingham,nottingham, United Kingdom, school of medicine,university of nottingham,nottingham, United Kingdom, school of medicine,university of nottingham,nottingham, United Kingdom, department of internal medicine,erasmus medical center,rotterdam, Netherlands, department of internal medicine,erasmus medical center,rotterdam, Netherlands, epidemiology division,family medicine and public health department,university of california,san diego,la jolla,ca, United States, respiratory,inflammation,autoimmunity innovative medicines,astrazeneca ab,mölndal, Sweden, nuffield department of orthopaedics,rheumatology and musculoskeletal sciences,university of oxford, United Kingdom, department of orthopaedics,leiden university medical center,leiden, Netherlands, department of rheumatology and department of clinical epidemiology,leiden university medical center,leiden, Netherlands, thurston arthritis research center,university of north carolina,chapel hill,nc, United States, university of california at san francisco,san francisco,ca, United States, department of medical statistics and bioinformatics,section molecular epidemiology,leiden university medical center,leiden, Netherlands, department of twins research and genetic epidemiology unit,king’s college london,london, United Kingdom, university medical center utrecht,utrecht, Netherlands, decode genetics,reykjavik, Iceland, wellcome trust sanger institute,hinxton, United Kingdom, department of hygiene & epidemiology,university of ioannina school of medicine,ioannina,greece,department of epidemiology and biostatistics,school of public health,imperial college london,london, United Kingdom, department of twins research and genetic epidemiology unit,king’s college london,london, United Kingdom, department of internal medicine,erasmus medical center,rotterdam,netherlands,department of epidemiology,erasmus medical center,rotterdam, Netherlands, university of california at san francisco,san francisco,ca,united states,school of medicine,university of california,davis,sacramento,ca, United States, department of medical statistics and bioinformatics,section molecular epidemiology,leiden university medical center,leiden, Netherlands, school of medicine,university of nottingham,nottingham, United Kingdom, department of internal medicine,erasmus medical center,rotterdam, Netherlands
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Authors
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