精神分裂癥相關(guān)單核苷酸多態(tài)性調(diào)控microRNA功能研究進(jìn)展

梁文權(quán)，侯豫，趙存友

精神分裂癥相關(guān)單核苷酸多態(tài)性調(diào)控microRNA功能研究進(jìn)展

梁文權(quán)1，侯豫2，趙存友1

1. 南方醫(yī)科大學(xué)基礎(chǔ)醫(yī)學(xué)院醫(yī)學(xué)遺傳學(xué)教研室，廣州 510515 2. 陸軍總醫(yī)院附屬八一兒童醫(yī)院神經(jīng)發(fā)育科，北京 100700

MicroRNA (miRNAs)是一類(lèi)長(zhǎng)約22nt且對(duì)基因表達(dá)具有廣泛的調(diào)控作用的非編碼RNA，并在神經(jīng)元增殖、分化和發(fā)育成熟的過(guò)程中扮演重要角色。近年來(lái)全基因組關(guān)聯(lián)研究(genome-wide association studies, GWAS)發(fā)現(xiàn)了眾多的精神分裂癥相關(guān)單核苷酸多態(tài)性(single nucleotide polymorphisms, SNPs)位點(diǎn)多位于非編碼區(qū)，表明miRNA在精神分裂癥的發(fā)病過(guò)程中存在重要作用。本文綜述了精神分裂癥相關(guān)SNP與miRNA可能發(fā)生相互作用的4種機(jī)制(SNP位于miRNA基因、SNP位于miRNA宿主基因、SNP位于miRNA種子序列和SNP位于miRNA結(jié)合位點(diǎn))，為研究miRNA在精神分裂癥發(fā)生發(fā)展中的作用提供參考。

全基因組關(guān)聯(lián)研究；單核苷酸多態(tài)性；微小RNA；精神分裂癥

精神分裂癥是多基因變異引發(fā)的復(fù)雜性遺傳病，也是最嚴(yán)重的精神類(lèi)疾病之一[1]。該疾病通常在青壯年時(shí)期發(fā)病，致殘率高，醫(yī)療資源消耗大，不僅影響患者的勞動(dòng)能力，而且給其家屬及社會(huì)造成嚴(yán)重負(fù)擔(dān)，因此探索行之有效的預(yù)防和治療措施，已經(jīng)成為一項(xiàng)全球性的社會(huì)和經(jīng)濟(jì)問(wèn)題。既往的遺傳學(xué)研究發(fā)現(xiàn)了若干與精神分裂癥相關(guān)的基因或位點(diǎn)，尤其近年來(lái)的全基因組關(guān)聯(lián)研究(genome-wide association study, GWAS)手段更是發(fā)現(xiàn)了大量與該疾病相關(guān)的單核苷酸多態(tài)性(single nucleotide poly-morphisms, SNPs)。然而，這些遺傳變異只有少數(shù)位于蛋白編碼區(qū)，更多的位于非編碼區(qū)，這使得研究者從基因表達(dá)調(diào)控角度研究疾病相關(guān)非編碼區(qū)的變異成為可能。已有多項(xiàng)報(bào)道發(fā)現(xiàn)與精神分裂癥相關(guān)的SNP位于microRNA (miRNA)的靶基因或結(jié)合位點(diǎn)，miRNA通過(guò)對(duì)上述基因或位點(diǎn)的負(fù)調(diào)控作用介導(dǎo)了精神分裂癥的發(fā)生和發(fā)展。

miRNA是一類(lèi)長(zhǎng)約22 nt的非編碼RNA，通過(guò)與靶基因mRNA 3?UTR區(qū)特異位點(diǎn)的結(jié)合使靶基因mRNA發(fā)生降解或翻譯阻遏[2,3]。當(dāng)位于靶基因3?UTR區(qū)的SNP位于miRNA的結(jié)合位點(diǎn)時(shí)，這會(huì)使miRNA與靶基因的結(jié)合能力發(fā)生改變，從而造成靶基因的表達(dá)或翻譯發(fā)生改變[4]。人類(lèi)mRNA 3?UTR擁有超過(guò)45 000個(gè)保守的miRNA結(jié)合位點(diǎn)，約60%的人類(lèi)蛋白質(zhì)編碼基因擁有至少一個(gè)保守的miRNA結(jié)合位點(diǎn)[5], 這些保守位點(diǎn)的堿基變異會(huì)影響到miRNA的調(diào)控功能。近年來(lái)采用GWAS手段發(fā)現(xiàn)的大量與精神分裂癥相關(guān)的SNPs多位于非編碼區(qū)，為從miRNA角度研究精神分裂癥的發(fā)病機(jī)制提供了線索。自2008年第1篇關(guān)于精神分裂癥GWAS分析的文章發(fā)表以來(lái)[6]，通過(guò)GWAS分析已發(fā)現(xiàn)許多與精神分裂癥相關(guān)的SNP[7~10]。對(duì)歐洲人群通過(guò)GWAS研究，發(fā)現(xiàn)基因內(nèi)含子區(qū)的SNP rs1625579與精神分裂癥相關(guān)[11]，在漢族人群中也得到了驗(yàn)證[12]。之后的研究支持為精神分裂癥危險(xiǎn)因素[13]，并且基因上的GWAS SNP rs1625579導(dǎo)致的等位基因表達(dá)不均一性[14]。Ning等[15]通過(guò)連鎖不平衡分析發(fā)現(xiàn)在中國(guó)漢族核心家系中基因座上的SNPs (rs1877670，rs3750192和rs7009708)構(gòu)建的單倍型與精神分裂癥顯著性關(guān)聯(lián)。越來(lái)越多的研究發(fā)現(xiàn)miRNA在神經(jīng)發(fā)育過(guò)程中調(diào)控基因表達(dá)，表明miRNA的表達(dá)改變可能會(huì)導(dǎo)致諸如精神分裂癥等精神疾病的發(fā)生。Perkins等[16]發(fā)現(xiàn)在精神分裂癥病人前額葉皮質(zhì)表達(dá)下降，基因位于22q11.2微缺失上，攜帶該微缺失的病人有1/4被確診為精神分裂癥患 者[17]。基因芯片研究發(fā)現(xiàn)在精神分裂癥患者的尸檢組織中顳上回和背外側(cè)前額葉中miRNAs的表達(dá)水平普遍增加[18]。遭遇童年創(chuàng)傷的精神分裂癥患者血液樣本中顯著下降，該miRNA在產(chǎn)前應(yīng)激的大鼠海馬組織中同樣發(fā)現(xiàn)表達(dá)顯著下降在[19]。研究發(fā)現(xiàn)和或、和對(duì)精神分裂癥具有較好的預(yù)測(cè)作用[20]。這些證據(jù)表明，精神分裂癥患者的miRNA表達(dá)譜發(fā)生改變是精神分裂癥發(fā)生發(fā)展的一個(gè)重要因素。

非編碼miRNA的調(diào)控功能為人們研究GWAS中發(fā)現(xiàn)的眾多非編碼區(qū)SNP的可能調(diào)控機(jī)制提供了新的線索。本文將從以下4個(gè)方面闡述與精神分裂癥相關(guān)的SNP通過(guò)miRNA實(shí)現(xiàn)對(duì)基因表達(dá)的調(diào)控作用(圖1)：(1) SNP位于miRNA基因：通過(guò)影響miRNA的表達(dá)量從而使下游的靶基因的表達(dá)量發(fā)生改變；(2) SNP位于miRNA的宿主基因：通過(guò)調(diào)控宿主基因的表達(dá)從而調(diào)控miRNA的表達(dá)量；(3) SNP位于miRNA的種子序列內(nèi)：影響miRNA與mRNA結(jié)合的穩(wěn)定性，使mRNA的穩(wěn)定性或翻譯受阻；(4) SNP位于miRNA靶基因的結(jié)合位點(diǎn)內(nèi)：通過(guò)改變miRNA與靶基因的結(jié)合能力從而調(diào)控靶基因的表達(dá)。

1 SNP位于miRNA基因

Ripke等[11]發(fā)現(xiàn)位于下游8 kb的rs1625579與精神分裂癥相關(guān)(=1.6×10–11)。另有研究發(fā)現(xiàn)在北美人群中攜帶TT基因型的精神分裂癥發(fā)病年齡較攜帶G基因的發(fā)病年齡提前，影像學(xué)研究發(fā)現(xiàn)攜帶TT基因型的人群腦白質(zhì)密度減少、海馬體積縮小以及側(cè)腦室增大[14]。研究表明，在腦組織中表達(dá)豐富[21]，與神經(jīng)元的分化與突觸可塑性相關(guān)，rs1625579及其連鎖的SNP (rs1198588、rs2660304和rs2802535)調(diào)控的表達(dá)量。Siegert等[22]研究發(fā)現(xiàn)擁有上述SNPs的minor-allele的神經(jīng)類(lèi)似細(xì)胞(neuron-like cells)的表達(dá)量上升，的上調(diào)使和的表達(dá)量下調(diào)導(dǎo)致突觸囊泡釋放功能異常[22]。

圖1 SNP通過(guò)miRNA實(shí)現(xiàn)對(duì)基因表達(dá)的調(diào)控

miRNA加工通路首先在細(xì)胞核內(nèi)經(jīng)RNA聚合酶Ⅱ或Ⅲ作用下產(chǎn)生初級(jí)miRNA轉(zhuǎn)錄本(pri-miRNA)，之后被Drosha-DGCR8 復(fù)合物裂解形成具有發(fā)夾結(jié)構(gòu)的前體miRNA(pre-miRNA)，并由Exportin-5-Ran-GTP復(fù)合物從細(xì)胞核中輸出。在細(xì)胞質(zhì)中，RNase Dicer和雙鏈RNA結(jié)合蛋白TRBP復(fù)合物共同作用將pre-miRNA發(fā)夾切割到成熟長(zhǎng)度。成熟miRNA的功能鏈與Argonaute (Ago2)蛋白一起加載到RNA誘導(dǎo)沉默復(fù)合物(RISC)中，引導(dǎo)RISC到靶向mRNA，進(jìn)而通過(guò)mRNA裂解、翻譯抑制或脫腺苷化沉默靶mRNA。在這一過(guò)程中，SNP通過(guò)miRNA實(shí)現(xiàn)對(duì)基因表達(dá)調(diào)控作用的4種主要機(jī)制是：(1) SNP位于miRNA基因；(2) SNP位于miRNA宿主基因；(3) SNP位于miRNA種子區(qū)域；(4) SNP位于miRNA結(jié)合位點(diǎn)。根據(jù)參考文獻(xiàn)[27]修改繪制。

Budach等[23]研究發(fā)現(xiàn)SNP位于miRNA的啟動(dòng)子中，提示SNP基因型的變化將對(duì)miRNA的表達(dá)量產(chǎn)生影響[23]。miRNA-eQTL多富集于miRNA的前體、啟動(dòng)子、增強(qiáng)子和轉(zhuǎn)錄因子結(jié)合區(qū)域，并且與其宿主基因的mRNA的eQTL存在大量交集。目前只有少量幾篇miRNA的eQTL數(shù)據(jù)發(fā)表，包括Parts等[24]發(fā)表的脂肪細(xì)胞的miRNA-eQTL、Siddle等[25]發(fā)表的樹(shù)突狀細(xì)胞的miRNA-eQTL和Huan 等[26]發(fā)現(xiàn)在全血中的miRNA-eQTL。上述研究表明位于miRNA的SNP可以調(diào)控miRNA的表達(dá)量，從而影響miRNA的下游調(diào)控通路，而使罹患精神分裂癥的風(fēng)險(xiǎn)上升。

2 SNP位于miRNA宿主基因

約40%的哺乳動(dòng)物miRNA位于其宿主基因的內(nèi)含子區(qū)[28]，有證據(jù)表明位于宿主基因內(nèi)含子區(qū)的miRNA的成熟并不需要Drosha酶的參與[29]。有研究表明被miRNA沉默的基因與miRNA的宿主基因在功能上具有拮抗作用，而miRNA的表達(dá)量與宿主基因的表達(dá)量呈正相關(guān)[30]；該研究還發(fā)現(xiàn)通過(guò)沉默與其宿主基因具有拮抗功能的和從而使對(duì)軸突生長(zhǎng)的刺激作用增強(qiáng)[30]。另外有研究檢測(cè)了和與其宿主基因在海馬神經(jīng)元成熟過(guò)程中的動(dòng)態(tài)表達(dá)變化，發(fā)現(xiàn)mRNA的3?UTR具有的結(jié)合位點(diǎn)，mimics轉(zhuǎn)染大鼠B35成神經(jīng)細(xì)胞瘤細(xì)胞發(fā)現(xiàn)的表達(dá)水平顯著降低，而轉(zhuǎn)染觀察不到該種現(xiàn) 象[31]。亦有研究報(bào)道多巴胺受體基因也是靶向基因，的缺失或的下調(diào)可導(dǎo)致22q11.2微缺失小鼠出現(xiàn)精神病性癥狀[32]。利用序列特異性miRNA海綿在發(fā)育期小鼠皮層中阻遏作用發(fā)現(xiàn)神經(jīng)元極性的丟失和皮層內(nèi)神經(jīng)元數(shù)目的減少，相反的，在皮層中過(guò)表達(dá)使神經(jīng)元的數(shù)目增加并且呈現(xiàn)多極性[33]。Ferrari等[34]發(fā)現(xiàn)6個(gè)SNPs (rs906175、rs2725391、rs969413、rs2659030、rs9319617和rs1048775)的致病基因型能降低的表達(dá)量。上述研究提示，位于miRNA宿主基因的SNP可能影響宿主基因的表達(dá)，從而使miRNA的表達(dá)異常；或者位于宿主基因的SNP影響miRNA的剪切成熟過(guò)程，從而使miRNA的表達(dá)異常；又或者位于宿主基因的SNP會(huì)使miRNA的轉(zhuǎn)錄調(diào)控機(jī)制異常，導(dǎo)致miRNA表達(dá)異常。不管如何，miRNA的表達(dá)異常，都有可能使罹患疾病的風(fēng)險(xiǎn)率上升。

3 SNP位于miRNA的種子序列內(nèi)

在成熟miRNA序列中5?端2~8位的堿基序列被稱為miRNA的種子序列，這一種子序列在miRNA與mRNA的識(shí)別與互補(bǔ)配對(duì)中扮演重要角色[35]。據(jù)統(tǒng)計(jì)，超過(guò)500個(gè)SNPs位于miRNA的種子序列，研究人員發(fā)現(xiàn)位于miRNA種子序列中心位置的SNP比位于種子序列外圍區(qū)域的少，因此miRNA種子序列中心區(qū)域在進(jìn)化上更保守[36]。研究表明即使是在miRNA種子序列的單個(gè)SNP變異也將導(dǎo)致大于50%的該miRNA靶基因頻譜變化[36]。目前還缺乏SNP位于miRNA種子序列導(dǎo)致精神分裂癥的直接證據(jù)，然而已有文章報(bào)道了這種SNP在其他疾病中的重要作用。Menc??a等[37]發(fā)現(xiàn)在內(nèi)耳毛細(xì)胞表達(dá)的種子序列的點(diǎn)突變將導(dǎo)致常染色體顯性遺傳的漸進(jìn)性失聰，種子序列的SNP (+13 G>A)將使下游靶基因、、、和表達(dá)發(fā)生改變。有研究表明在種子序列的SNP (+57C>T)能夠?qū)е翬DICT (endoth-elial dystrophy, congenital cataract, and stromal thinning)綜合征[38]。Jiang等[39]研究發(fā)現(xiàn)有617個(gè)SNPs位于牛源的331個(gè)成熟miRNAs的種子序列內(nèi)，位于種子序列的SNP (rs109462250)因?yàn)榻Y(jié)合位點(diǎn)的改變影響的表達(dá)，通過(guò)雙熒光驗(yàn)證了rs109462250的42198 087 G>A突變使與的結(jié)合能力降低。Chai等[40]發(fā)現(xiàn)位于種子序列的SNP(rs331295049 A17G)使的表達(dá)上調(diào)(miR-378/G)，并且該SNP改變了的二級(jí)結(jié)構(gòu)，使其對(duì)原有85%靶基因失去調(diào)控作用，但同時(shí)又產(chǎn)生了700多個(gè)新的靶基因。上述研究表明，位于miRNA種子序列的SNP具有十分重要的生物學(xué)作用，然而現(xiàn)在缺乏SNP位于miRNA種子序列內(nèi)導(dǎo)致精神分裂癥患病風(fēng)險(xiǎn)上升的相關(guān)報(bào)道。

4 SNP位于miRNA結(jié)合位點(diǎn)內(nèi)

據(jù)報(bào)道，大約5%的miRNA識(shí)別元件(miR recognition element, MRE)中具有SNP，約3%的miRNA識(shí)別元件種子序列((miR recognition element seed sites, MRESS)具有SNP，同時(shí)研究表明約38%的MRESS-SNP位于8mer MRESSs[41]。

位于靶基因mRNA 3?UTR區(qū)miRNA結(jié)合位點(diǎn)內(nèi)的SNP將會(huì)影響miRNA與mRNA的結(jié)合，從而使miRNA對(duì)mRNA的調(diào)控過(guò)程受阻。近年來(lái)，人們已經(jīng)發(fā)現(xiàn)若干個(gè)位于miRNA結(jié)合位點(diǎn)的SNP對(duì)精神分裂癥的發(fā)生發(fā)展具有影響。Hou等[42]通過(guò)對(duì)GWAS精神分裂癥相關(guān)變異位點(diǎn)的檢索發(fā)現(xiàn)，位于基因3?UTR區(qū)rs4702-G可通過(guò)增加的結(jié)合能力而參與FURIN的表達(dá)下調(diào)，而FURIN的表達(dá)量降低將導(dǎo)致成熟腦源性神經(jīng)營(yíng)養(yǎng)因子(brain derived neurotrophic factor，BDNF)的生成減少，后者的降低已經(jīng)報(bào)道與精神分裂癥的發(fā)生相關(guān)。Gong等[4]發(fā)現(xiàn)在精神分裂癥患者中rs10759-C將降低miR-124與RGS4 mRNA結(jié)合的最小自由能(minimum free energy, MFE)，從而使與mRNA的結(jié)合更加穩(wěn)定，顯著降低RGS4的表達(dá)量。Rossi等[43]發(fā)現(xiàn)rs11122396位于3? UTR區(qū)，且位于的結(jié)合位點(diǎn)，通過(guò)雙熒光素酶報(bào)告載體證實(shí)了rs11122396對(duì)結(jié)合mRNA的影響，且他們認(rèn)為SNP對(duì)miRNA的影響是有等位基因差異的，即SNP只對(duì)miRNA結(jié)合其中一條染色體轉(zhuǎn)錄的mRNA有影響，對(duì)另外一條染色體轉(zhuǎn)錄的mRNA無(wú)影響，簡(jiǎn)稱等位基因差異性調(diào)控。Hauberg等[23]發(fā)現(xiàn)rs11191548能影響與mRNA的結(jié)合，從而影響NT5C2的表達(dá)，且通過(guò)雙熒光素酶報(bào)告載體驗(yàn)證; 值得注意的是是所有保守miRNA中對(duì)精神分裂癥易感基因有明顯調(diào)節(jié)作用的miRNA之一[44]。研究證明位于3?-UTR的SNP(rs1060120)將影響對(duì)H3F3B的轉(zhuǎn)錄后調(diào)控，并且可能參與的精神分裂癥的發(fā)生[45]。John等[46]在精神分裂癥病人樣本中驗(yàn)證了35個(gè)位于精神分裂癥相關(guān)基因3?-UTR miRNA結(jié)合位點(diǎn)上的SNPs，研究發(fā)現(xiàn)位于3?-UTR的rs7430與精神分裂癥具有顯著相關(guān)性(= 0.01; OR (95%) 1.24 (1.04~1.48))。位于3?-UTR的rs550067317將影響miR-137對(duì)EFNB2的調(diào)控能力[47]。上述研究表明位于miRNA結(jié)合區(qū)域的SNP將會(huì)使miRNA與mRNA的結(jié)合能發(fā)生變化，從而影響miRNA與RNA的結(jié)合，使miRNA對(duì)mRNA的調(diào)控發(fā)生異常。

5 SNP對(duì)miRNA調(diào)控過(guò)程影響的預(yù)測(cè)方法

研究SNP與miRNA的相互作用，可能需要利用生物信息學(xué)方法對(duì)miRNA的靶基因以及SNP與miRNA的關(guān)系進(jìn)行預(yù)測(cè)。因?yàn)閙iRNA能調(diào)控?cái)?shù)百個(gè)靶基因，所以研究miRNA最大的困難是預(yù)測(cè)miRNA的靶基因，現(xiàn)有的miRNA靶基因預(yù)測(cè)軟件或網(wǎng)站如表1。

現(xiàn)有的預(yù)測(cè)軟件或網(wǎng)站只能從生物信息學(xué)方面預(yù)測(cè)位于miRNA結(jié)合位點(diǎn)或種子序列的SNP對(duì)miRNA結(jié)合mRNA的影響，具體的功能還需要構(gòu)建熒光報(bào)告載體驗(yàn)證。同樣，人們也可以通過(guò)過(guò)表達(dá)miRNA結(jié)合ChIP-seq的方式獲得miRNA結(jié)合的mRNA的序列信息，然而其生物學(xué)功能仍需構(gòu)建熒光報(bào)告載體和基因敲降實(shí)驗(yàn)進(jìn)行驗(yàn)證。還可以通過(guò)CRISPR/Cas9獲得不同基因型的細(xì)胞，從而驗(yàn)證miRNA對(duì)位于mRNA 3? UTR的不同基因型SNP的作用或驗(yàn)證不同基因型對(duì)miRNA表達(dá)或剪切成熟過(guò)程的影響或位于miRNA種子序列不同基因型SNP對(duì)其下游通路的影響。最后可以構(gòu)建轉(zhuǎn)基因動(dòng)物模型從而驗(yàn)證不同基因型SNP罹患精神分裂癥的風(fēng)險(xiǎn)。

表1 miRNA靶基因預(yù)測(cè)軟件或網(wǎng)站

6 結(jié)語(yǔ)與展望

miRNA在大腦中的廣泛性表達(dá)和在精神分裂癥中的表達(dá)紊亂，提示miRNA與精神分裂癥存在相關(guān)性。近年來(lái)多篇GWAS的研究結(jié)果為人們解析精神分裂癥的致病機(jī)制提供了許多可能的具有生物學(xué)功能的遺傳變異資源，然而在后GWAS時(shí)代如何去驗(yàn)證GWAS報(bào)道的SNP卻十分困難，因?yàn)殡m然有部分SNP位于蛋白質(zhì)編碼區(qū)，然而也有一部分位于非編碼區(qū)，如何去驗(yàn)證位于非編碼區(qū)的SNP的生物學(xué)功能至今是一個(gè)難題。已有研究證明miRNA與GWAS-SNPs存在相互作用，提示位于非編碼區(qū)域的GWAS-SNPs可能在轉(zhuǎn)錄調(diào)控或轉(zhuǎn)錄后調(diào)控的過(guò)程中具有重要的生物學(xué)作用，例如位于宿主基因的SNPs可能影響miRNA的表達(dá)從而改變下游靶基因的表達(dá)，位于miRNA基因上的SNPs直接導(dǎo)致miRNA表達(dá)異常參與了精神分裂癥的發(fā)生與發(fā)展，位于種子序列的SNPs可能導(dǎo)致mRNA表達(dá)譜的改變從而導(dǎo)致精神分裂癥的發(fā)生，位于結(jié)合位點(diǎn)的SNPs可能是miRNA與靶基因的轉(zhuǎn)錄后調(diào)控過(guò)程發(fā)生異常導(dǎo)致精神分裂癥的發(fā)生。

精神分裂癥作為一種重性精神疾病，在我國(guó)“十三五”腦計(jì)劃提出的大背景下必將受到更多的關(guān)注，精神分裂癥作為環(huán)境與遺傳因素共同作用的多基因遺傳病，或許miRNA結(jié)合SNP的研究是闡明精神分裂癥病理過(guò)程的更好的切入點(diǎn)，為以后臨床診斷和治療精神分裂癥提供理論基礎(chǔ)。盡管GWAS研究已經(jīng)發(fā)現(xiàn)許多與精神分裂癥相關(guān)的SNP，但如何驗(yàn)證其功能仍將是未來(lái)的一個(gè)研究熱點(diǎn)，此外將miRNA與精神分裂癥相關(guān)SNP結(jié)合在一起，從遺傳學(xué)和表觀遺傳學(xué)角度闡明精神分裂癥的發(fā)病機(jī)制也將會(huì)是未來(lái)研究的一個(gè)重要發(fā)展方向。

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Schizophrenia-associated single nucleotide polymorphisms affecting microRNA function

Wenquan Liang1, Yu Hou2, Cunyou Zhao1

MicroRNAs (miRNAs) compose a class of non-coding transcripts with a mean length of 22 nucleotides, and play critical roles in regulating gene expression in the process of development, proliferation and differentiation of neurons. Recent genome-wide association studies (GWAS) find most of schizophrenia-associated single nucleotide polymorphisms (SNPs) locating in the non-coding regions, providing functional implications of miRNAs in the development of schizophrenia. In this review, we highlight the interplays between GWAS-SNPs and miRNAs in four perspectives: SNP in miRNA gene; miRNA located in the host gene; SNP located in the miRNA’s seed sequence; SNP located in the miRNA’s binding site. We also speculate on the future research on the role of miRNA in the development of schizophrenia.

GWAS; SNP; miRNA; schizophrenia

2019-05-08;

2019-07-07

廣東省科技計(jì)劃項(xiàng)目(編號(hào)：2019B030316032)，廣州市科技計(jì)劃項(xiàng)目(編號(hào)：201804010259)和國(guó)家自然科學(xué)基金項(xiàng)目(編號(hào)：81601175，81671333)資助[Supported by the Guangdong Science and Technology Foundation (No. 2019B030316032), the Guangzhou Science and Technology Foundation (No. 201804010259) and the National Natural Science Foundation of China (Nos. 81601175, 81671333)]

梁文權(quán)，碩士在讀研究生，專業(yè)方向：表觀遺傳。E-mail: wen1390229749@163.com

趙存友，博士，教授，研究方向：表觀遺傳。E-mail: cyzhao@smu.edu.cn

10.16288/j.yczz.19-126

2019/8/5 20:59:49

URI: http://kns.cnki.net/kcms/detail/11.1913.R.20190805.2059.003.html

(責(zé)任編委: 夏昆)