Autism Pathway Network Analyses Identify Overlaps with Other Disease Groups, Involve Many Functions and Converge upon MAPK and Calcium Signaling

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https://imfar.confex.com/imfar/2016/webprogram/Paper22096.html

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12/16/2016
2016 International Meeting for Autism Research: Autism Pathway Network Analyses Identify Overlaps with Other Disease Groups, Involve Many Functions …
https://imfar.confex.com/imfar/2016/webprogram/Paper22096.html 1/3
22096
AutismPathwayNetworkAnalysesIdentifyOverlapswithOtherDiseaseGroups,
InvolveManyFunctionsandConvergeuponMAPKandCalciumSignaling
Friday,May13,2016:11:30AM1:30PM
HallA(BaltimoreConventionCenter)
Y.Wen ,M.Alshikho andM.R.Herbert ,(1)Neurology(Pediatric),HarvardMedical
School,Boston,MA,(2)HigherSynthesisFoundation,Cambridge,MA,(3)Neurology,
MassachusettsGeneralHospital,Charlestown,MA
Background:Autismspectrumdisorders(ASDs)encompassmanyetiologiesandheterogeneous
phenotypesbroughttogetherbycommonbehavioralfeaturesandemergenceduringearly
development.AsofDecember2014,theSFARI(SimonsFoundationAutismResearchInitiative)
GeneHumanGeneModulerecorded667humangenesimplicatedasrelevanttoASDswhose
diversitychallengeseffortsatidentifyingcoherentbiologicalmechanisms.
Objectives:Identifyingconvergentmolecularpathwaysinwhichmultiplecandidategenesare
involvedmaybeaneffectivewaytogaininsightintotheunderlyingmolecularbasesofASDs.We
soughttocombineinformationfromseveralexistingandwellestablisheddatabasesto
contextualizeautismassociatedgenesinrelationtothefunctionsofgeneproducts,the
networkingofreactions,pathwaypathwayandgenepathwayinteractions,anddiseasedisease
relationships.
Methods:WefirstinvestigatedenrichmentwithintheHumanGeneModuleofSFARIGene,by
computingoverlapsbetweenSFARIgenesandMSigDB(MolecularSignaturesDatabase,v4.0)
genesetderivedfromKEGG(KyotoEncyclopediaofGenesandGenomes)PathwayDatabase.This
allowedustogeneratearankedlistofthetop50pathwayswithinwhichtheASDgeneswere
enriched.WethenappliedRedundancyControlinPathwayDatabases(ReCiPa)totheenriched
pathwaylist,tominimizetheimpactofpotentialredundancycausedbysomehighlyoverlapped
pathways,whichweremergedascollections,yieldingafinallistof40pathways,groupedin
DiseaseandFunctioncategories.KEGGpathwaymapswereusedtoidentifytheinteractions
amongpathways,whichwerefullydepictedinapathwaynetworkmap.Therelativefrequenciesof
representationofcomponentsofthepathwaynetworkwerequantitativelyrankedandassessedby
tabulatingthenumberofinteractionseachpathwayhadwithinthenetwork.Noweightingwas
appliedastherewerenostandardmethodsavailable.
Results:“Calciumsignalingpathway”(pvalue2.84E29)and“neuroactiveligandreceptor
interaction”(pvalue2.87E29)werethemostenriched,statisticallysignificantpathwaysfromthe
enrichmentanalysis.Pathwaysweregroupedinto10diseasepathways:cancer(4/10),
neurodegenerative(3/10),cardiac(2/10)metabolicdiseases(1/10);and30functionalpathways:
cellsignaling(9/10),cellstructure/transport(5/30),immune(3/30),neural(5/30)metabolism
(8/30).PerturbationsassociatedwithKEGG’scategoryofenvironmentalinformationprocessing
werecommon.Thetwomostinteractivepathways,MAPKsignalingpathwayandcalciumsignaling
pathways,interactedwith20/40and12/40pathwaysrespectively.
1,2,3 1,3 1,2,3

12/16/2016
2016 International Meeting for Autism Research: Autism Pathway Network Analyses Identify Overlaps with Other Disease Groups, Involve Many Functions …
https://imfar.confex.com/imfar/2016/webprogram/Paper22096.html 2/3
When:
Conclusions:Ourkeyfindings,derivedfrommethodsfreeofaprioriassumptionsregarding
relevancetoautism,demonstratemarkedoverlapbetweenASDgenes/pathwaysandthose
associatedwithotherdiseases,andindicatethatenvironmentalinformationprocessingisbroadly
impacted.FindingsconvergeduponMAPKsignalingandcalciumsignalingpathways—whichimpact
alargerangeofbiologicalprocessesinvolvedinmanyfunctionsanddiseases—asinteractivehubs
intheautismpathwaynetwork.Thesefindingssupporttheideathat,baseduponpotential
compromiseofmanytypesofbiologicaloutput,autismassociatedgenesmaycontributenotonly
tocorefeaturesofautismthemselvesbutalsotovulnerabilitytootherchronicandsystemic
problemspotentiallyincludingcancer,metabolicconditionsandheartdiseases.ASDsmaythus
arise,oremerge,fromunderlyingvulnerabilitiesrelatedtopleiotropicgenesassociatedwith
pervasivelyimportantmolecularmechanisms,perturbedenvironmentalinformationprocessingand
multiplesystemiccomorbidities.
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12/16/2016
2016 International Meeting for Autism Research: Autism Pathway Network Analyses Identify Overlaps with Other Disease Groups, Involve Many Functions …
https://imfar.confex.com/imfar/2016/webprogram/Paper22096.html 3/3
When:
May1114,2016
Where:
BaltimoreConventionCenter
Baltimore,MD
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Presentedat:2016InternationalMeetingforAutismResearch