NatureGeNeticsVOLUME49|NUMBER5|MAY2017801Weperformedagenome-wideassociationstudyoftotalhipreplacements,basedonvariantsidentifiedthroughwhole-genomesequencing,whichincluded4,657Icelandicpatientsand207,514populationcontrols.Wediscoveredtworaresignalsthatstronglyassociatewithosteoarthritistotalhipreplacement:amissensevariant,c.1141G>C(p.Asp369His),intheCOMPgene(allelicfrequency=0.026%,P=4.0×10−12,oddsratio(OR)=16.7)andaframeshiftmutation,rs532464664(p.Val330Glyfs*106),intheCHADLgenethatassociatesthrougharecessivemodeofinheritance(homozygotefrequency=0.15%,P=4.5×10−18,OR=7.71).Onaverage,c.1141G>Cheterozygotesandindividualshomozygousforrs532464664hadtheirhipreplacementoperation13.5yearsand4.9yearsearlierthanothers(P=0.0020andP=0.0026),respectively.Weshowthatthefull-lengthCHADLtranscriptisexpressedincartilage.Furthermore,theprematurestopcodonintroducedbytheCHADLframeshiftmutationresultsinnonsense-mediateddecayofthemutanttranscripts.Osteoarthritisisahighlyheterogeneousdiseaseorasetofdisor-derswithagreatimpactonthequalityoflife.Osteoarthritisisadiseaseoftheentirejoint,affectingcartilage,synovium,subchon-dralbone,ligamentsandthejointcapsule1.Totalhipreplacement(THR)isatreatmentforsevereosteoarthritisofthehip,indicatedbyseverepainandreducedmobility,althoughradiographicchangesinthesesubjectsmayvary.Genome-wideassociationstudies(GWAS)ofhiposteoarthritishavereportedanumberofcommonsequencevariants,allconferringsmalltomoderateeffects2–7.HerewereportonaGWASyieldingtworaresequencevariantsthatassociatewithend-stagehiposteoarthritis(THR).Weincluded4,657IcelanderswhounderwentTHRbecauseofosteoarthritisascasesand207,514individualsaspopulationcontrolsintheGWAS.Thesequencevariantsincludedintheanalyseswereidentifiedthroughwhole-genomesequencingof8,453Icelandersandsubsequentlyimputedinto150,656individualswhohadbeenchip-typedandtheirfirst-andsecond-degreerelatives.WethentestedforassociationbetweenTHRandthesesequencevariants(31.6millionvariantsunderthemultiplicativemodeland19.2millionv...
