Shangyun Shi, Ancha Baranova, Hongbao Cao, Fuquan Zhang
Alpha Psychiatry - 2025;26(6):1-10
Background : Inautismspectrumdisorder(ASD),thehumanplasmametabolomeisalteredbutthecausalrelationshipbetweenthelevels ofmetabolitesandASDisunclear. WeaimedtoassessbidirectionalcausalassociationsbetweenplasmametabolitesandASD. Meth- ods: We investigated potential causal associations between the genetic variation contributing to the levels of metabolites and ASD via Mendelianrandomization(MR)analyses. Genome-wideassociationstudy(GWAS)summarydatasetswereusedinthestudy,including ASD(n=46,350)and871plasmametabolite(n=8299)datasets. Weuseddruggabilityanalysistoprioritizemetaboliteswiththerapeuticpotential. Results: OurMRanalysisidentified32plasmametaboliteswhoselevelswereprotectiveagainsttheriskofASD,including5alpha-androstan-3alpha,17beta-dioldisulfate(oddsratio(OR):0.94,95%CI:0.90-0.97)and11beta-hydroxyetiocholanoloneglucuronide(OR:0.95,95%CI:0.92-0.98).Additionally,12metaboliteswerefoundtobepositivelyassociatedwiththeriskofASD,includingindoleacetylglutamine(OR:1.04,95%CI:1.01-1.08)andsphingomyelin(d18:1/24:1,d18:2/24:0)(OR:1.06,95%CI:1.01-1.11).Somemetabolitesmayberegulatedthroughdrugintervention,includingsphingomyelin,chiro-inositol,carotenediol(1)/(2),andglycerol.GeneticvariationcontributingtoASDmayincreasetheabundanceoffivemetabolites,includingdeoxycholicacidglucuronide(OR:1.18,95%CI:1.03-1.34);meanwhile,theabundanceof27metabolites,includingstearoylcholine(OR:0.80,95%CI:0.69-0.92)maybecausallyreduced. Conclusions : OurMRanalysisuncoveredbidirectionalcausalassociationsbetweencertainplasmametabo- litesandASD,suggestingthatthesemetabolitescouldbebiomarkersforASDandpavingthewayfornoveltherapeutictargetsinASDphenotypes.
