大规模外显子组测序揭示自闭症中神经发育和功能的变化
2020-02-05   阅读:331   来源:Cell

美国西奈山伊坎医学院JosephD.Buxbaum、博德研究所MarkJ.Daly、卡内基梅隆大学KathrynRoeder、加州大学旧金山分校StephanJ.Sanders等研究人员通过大规模外显子组测序,揭示了自闭症神经生物学中的发育和功能变化。相关论文2020年1月23日在线发表在《细胞》上。

研究人员报道了迄今为止最大的自闭症谱系障碍(ASD)外显子组测序研究(n=35584的总样本,其中11986例患有ASD)。使用增强的分析框架整合从头的以及病例对照的罕见变异,研究人员以0.1或更低的错误发现率鉴定了102个风险基因。在这些基因中,有49个在被确定具有严重神经发育迟缓的个体中显示出更高的破坏性从头变体频率,而53个在被确定具有ASD的个体中表现出较高的频率。比较这些组中具有突变的ASD病例可发现表型差异。在大脑发育早期表达的大多数风险基因在基因表达或神经元沟通的调节中起作用(即突变影响神经发育和神经生理学变化),并且有13个属于拷贝数变异反复出现的基因座。在人类皮层细胞中,风险基因的表达富集在兴奋性和抑制性神经元谱系中,这与导致ASD的兴奋性抑制性失衡的多种途径一致。

附:英文原文

Title:Large-ScaleExomeSequencingStudyImplicatesBothDevelopmentalandFunctionalChangesintheNeurobiologyofAutism

Author:F.KyleSatterstrom,JackA.Kosmicki,JiebiaoWang,MichaelS.Breen,SilviaDeRubeis,Joon-YongAn,MinshiPeng,RyanCollins,JakobGrove,LambertusKlei,ChristineStevens,JenniferReichert,MaureenS.Mulhern,MykytaArtomov,SherifGerges,BrookeSheppard,XinyiXu,AparnaBhaduri,UtkuNorman,HarrisonBrand,GraceSchwartz,RachelNguyen,ElizabethE.Guerrero,CarolineDias,BrankoAleksic,RichardAnney,MafaldaBarbosa,SomerBishop,AlfredoBrusco,JonasBybjerg-Grauholm,AngelCarracedo,MarcusC.Y.Chan,AndreasG.Chiocchetti,BrianH.Y.Chung,HilaryCoon,MichaelL.Cuccaro,AuroraCurró,BernardoDallaBernardina,RyanDoan,EnricoDomenici,ShanDong,ChiaraFallerini,MontserratFernández-Prieto,GiovanniBattistaFerrero,ChristineM.Freitag,MenachemFromer,J.JayGargus,DanielGeschwind,ElisaGiorgio,JavierGonzález-Peas,StephenGuter,DanielleHalpern,EmilyHansen-Kiss,XinHe,GailE.Herman,IrvaHertz-Picciotto,DavidM.Hougaard,ChristinaM.Hultman,IulianaIonita-Laza,SumaJacob,JesslynJamison,AstanandJugessur,MiiaKaartinen,GunPeggyKnudsen,AlexanderKolevzon,ItaruKushima,SoLunLee,TerhoLehtimki,ElaineT.Lim,CarlaLintas,W.IanLipkin,DiegoLopergolo,FátimaLopes,YuninLudena,PatriciaMaciel,PerMagnus,BehrangMahjani,NellMaltman,DaraS.Manoach,GalMeiri,IdanMenashe,JudithMiller,NancyMinshew,EduardaM.S.Montenegro,DanielleMoreira,EricM.Morrow,OleMors,PrebenBoMortensen,MatthewMosconi,PierandreaMuglia,BenjaminM.Neale,MereteNordentoft,NorioOzaki,AarnoPalotie,MaraParellada,MariaRitaPassos-Bueno,MargaretPericak-Vance,AntonioM.Persico

Issue&Volume:January23,2020

Abstract:Wepresentthelargestexomesequencingstudyofautismspectrumdisorder(ASD)todate(n=35,584totalsamples,11,986withASD).Usinganenhancedanalyticalframeworktointegratedenovoandcase-controlrarevariation,weidentify102riskgenesatafalsediscoveryrateof0.1orless.Ofthesegenes,49showhigherfrequenciesofdisruptivedenovovariantsinindividualsascertainedtohavesevereneurodevelopmentaldelay,whereas53showhigherfrequenciesinindividualsascertainedtohaveASD;comparingASDcaseswithmutationsinthesegroupsrevealsphenotypicdifferences.Expressedearlyinbraindevelopment,mostriskgeneshaverolesinregulationofgeneexpressionorneuronalcommunication(i.e.,mutationseffectneurodevelopmentalandneurophysiologicalchanges),and13fallwithinlocirecurrentlyhitbycopynumbervariants.Incellsfromthehumancortex,expressionofriskgenesisenrichedinexcitatoryandinhibitoryneuronallineages,consistentwithmultiplepathstoanexcitatory-inhibitoryimbalanceunderlyingASD.

DOI:10.1016/j.cell.2019.12.036

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