DRD2 and PPP1R1B (DARPP-32) polymorphisms independently confer increased risk for autism spectrum disorders and additively predict affected status in male-only affected sib-pair families.docVIP

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DRD2 and PPP1R1B (DARPP-32) polymorphisms independently confer increased risk for autism spectrum disorders and additively predict affected status in male-only affected sib-pair families.doc

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DRD2 and PPP1R1B (DARPP-32) polymorphisms independently confer increased risk for autism spectrum disorders and additively predict affected status in male-only affected sib-pair families

Hettingeretal.BehavioralandBrainFunctions2012,8:19 /8/1/19 RESEARCH OpenAccess DRD2andPPP1R1B(DARPP-32 )polymorphisms independentlyconferincreasedriskforautism spectrumdisordersandadditivelypredict affectedstatusinmale-onlyaffectedsib-pair families JoeAHettinger1,XudongLiu2,3,MelissaLHudson2,3,4,AlanaLee2,3,4,IraLCohen4,5,RonCMichaelis6, CharlesESchwartz7,SuzanneMELewis4,8,9andJeanetteJAHolden1,2,3,4,10,11* Abstract Background:Theneurotransmitterdopamine(DA)modulatesexecutivefunctions,learning,andemotional processing,allofwhichareimpairedinindividualswithautismspectrumdisorders(ASDs).Ourpreviousfindings suggestarolefordopamine-relatedgenesinfamilieswithonlyaffectedmales. Methods:WeexaminedtwoadditionalgeneswhichaffectDAfunction,theDRD2andPPP1R1B(DARPP-32 )genes, inacohortof112male-onlyaffectedsib-pairfamilies.Selectedpolymorphismsspanningthesegeneswere genotypedandbothfamily-basedandpopulation-basedtestswerecarriedoutforassociationanalysis.General discriminantanalysiswasusedtoexaminethegene-geneinteractionsinpredictingautismsusceptibility. Results:TherewasasignificantlyincreasedfrequencyoftheDRD2rs1800498TTgenotype(P=0.007)inaffected malescomparedtothecomparisongroup,apparentlyduetoover-transmissionoftheTallele(P=0.0003).The frequencyofthePPP1R1Brs1495099CCgenotypeinaffectedmaleswasalsohigherthanthatinthecomparison group(P=0.002)duetopreferentialtransmissionoftheCallelefromparentstoaffectedchildren(P =0.0009). Allelesrs1800498Tandrs1495099Cwereassociatedwithmoresevereproblemsinsocialinteraction(P=0.0002and P=0.0016,respectively)andcommunication(P=0.0004andP=0.0046),andincreasedstereotypicbehaviours (P=0.0021andP=0.00072).GeneraldiscriminantanalysisfoundthattheDRD2andPPP1R1Bgenesadditively predictedASDs(P=0.00011;CanonicalR=0.26)andexplain~7%ofthevarianceinourfamilies.Allfindings remainedsignificantfollowingcorrectionsformultipletesting. Conclusion:OurfindingssupportarolefortheDRD2andPPP1R1Bgenesinconferringriskforautisminfamilies withonlyaffectedmalesandshowanaddi