劉興彥, 李 明, 楊順英, 宿 兵, 尹利德,

(1. 玉溪市第二人民醫(yī)院, 玉溪 653101; 2. 中國(guó)科學(xué)院昆明動(dòng)物研究所 遺傳資源與進(jìn)化國(guó)家重點(diǎn)實(shí)驗(yàn)室, 昆明 650223; 3. 中國(guó)科學(xué)院研究生院, 北京 100049）

中國(guó)漢族人群中RELN基因rs7341475位點(diǎn)與精神分裂癥的相關(guān)性分析

劉興彥1, 李 明2,3, 楊順英1, 宿 兵2,*, 尹利德1,*

(1. 玉溪市第二人民醫(yī)院, 玉溪 653101; 2. 中國(guó)科學(xué)院昆明動(dòng)物研究所 遺傳資源與進(jìn)化國(guó)家重點(diǎn)實(shí)驗(yàn)室, 昆明 650223; 3. 中國(guó)科學(xué)院研究生院, 北京 100049）

精神分裂癥是一種常見(jiàn)的復(fù)雜精神疾病。大量的實(shí)驗(yàn)證據(jù)表明, 遺傳因素在精神分裂癥的發(fā)生中起到了重要的作用。截至目前, 有報(bào)道稱至少 100個(gè)基因與精神分裂癥相關(guān), 但它們?cè)诓煌巳褐械闹貜?fù)性不好。在這些基因中,RELN在多個(gè)人群中都被證實(shí)與精神分裂癥相關(guān), 表明它可能是一個(gè)真實(shí)的易感基因。目前, 在RELN基因上有很多個(gè)單核苷酸多態(tài)性位點(diǎn)被證實(shí)與精神分裂癥相關(guān), 其中研究最多的是通過(guò)全基因組關(guān)聯(lián)分析發(fā)現(xiàn)的在RELN基因第四個(gè)內(nèi)含子中的單核苷酸多態(tài)性位點(diǎn) rs7341475, 它被證明與精神分裂癥的發(fā)生相關(guān)。為了驗(yàn)證該位點(diǎn)在中國(guó)人群中是否與精神分裂癥相關(guān), 作者對(duì)來(lái)自中國(guó)玉溪的病例——對(duì)照樣本(400位患者和400位正常人)進(jìn)行了遺傳分析。結(jié)果顯示, 在該樣本中rs7341475與精神分裂癥不相關(guān), 這表明rs7341475在中國(guó)人群中可能不是致病多態(tài)性位點(diǎn)。

精神分裂癥;RELN; 單核苷酸多態(tài)性位點(diǎn); 中國(guó)人群

精神分裂癥是以基本個(gè)性的改變, 思維、情感、行為的分裂以及精神活動(dòng)與環(huán)境的不協(xié)調(diào)為主要特征的一類(lèi)最常見(jiàn)的精神疾病 (Andreasen, 1995)。流行病學(xué)調(diào)查表明, 精神分裂癥在不同人群中的流行率相近, 都約為1% (Freedman, 2003)。精神分裂癥的病因到目前仍不清楚, 但已有的數(shù)據(jù)表明, 遺傳因素和環(huán)境因素都起作用。家系、雙胞胎和領(lǐng)養(yǎng)研究證明, 精神分裂癥具有很強(qiáng)的遺傳傾向, 其遺傳力可達(dá)80%～85% (Lichtenstein et al, 2009)。即使精神分裂癥有如此高的遺傳傾向, 對(duì)于探索它的易感基因的努力卻收獲很小。截至目前, 至少有100個(gè)基因被報(bào)道與精神分裂癥相關(guān), 卻只有少數(shù)幾種基因能持續(xù)在世界上不同人群中印證相關(guān)性, 包括DISC1、COMT、BDNF和NRG1等 (Georgieva et al, 2008; Hennah et al, 2009; Neves-Pereira et al, 2005; Shifman et al, 2002)。此外, 在探索精神分裂癥的易感基因中, 全基因組關(guān)聯(lián)分析被證明是成功的, 通過(guò)這種手段報(bào)道了數(shù)個(gè)新的精神分裂癥易感基因，包括ZNF804A、TCF4、NRGN和MHC區(qū)域等(O'Donovan et al, 2008; Purcell et al, 2009; Shi et al, 2009; Stefansson et al, 2009)。

在早期的研究中, 通過(guò)全基因組連鎖分析的方法在染色體7q22位置上發(fā)現(xiàn)精神分裂癥易感的短重復(fù)序列, 而這些短重復(fù)序列正位于RELN基因內(nèi) (Ekelund et al, 2000; Wedenoja et al, 2008)。與此同時(shí),RELN在精神分裂癥患者腦中表達(dá)量出現(xiàn)了下降 (Eastwood & Harrison, 2006; Fatemi et al, 2000; Guidotti et al, 2000; Impagnatiello et al, 1998), 表明RELN基因可能參與了精神分裂癥的發(fā)生。隨后, 在歐洲人群中發(fā)現(xiàn)了多個(gè)RELN基因上的單核苷酸多態(tài)性位點(diǎn)與精神分裂癥相關(guān)(Kahler et al, 2008), 并尋找出了其他位點(diǎn)與精神分裂癥的表型顯著相關(guān) (Wedenoja et al, 2008, 2010)。因此, 這些都表明了RELN基因與精神分裂癥的發(fā)生相關(guān), 但是真正的致病多態(tài)性位點(diǎn)并沒(méi)有被發(fā)現(xiàn)。

Shifman et al（2008)用全基因組關(guān)聯(lián)分析的方法, 發(fā)現(xiàn)RELN基因第四個(gè)內(nèi)含子中的單核苷酸多態(tài)性位點(diǎn)(rs7341475)在猶太女性人群及英國(guó)女性人群中與精神分裂癥顯著相關(guān)。隨后, 這個(gè)位點(diǎn)(rs7341475)在另一份猶太人樣本中也被證實(shí)與精神分裂癥相關(guān) (Liu et al, 2010; Pisante et al, 2009); 但這個(gè)位點(diǎn)在其他人群中則并不與精神分裂癥相關(guān)(Need et al, 2009)。這些都表明rs7341475與精神分裂癥相關(guān), 但存在種族異質(zhì)性。為了研究RELN基因的這個(gè)位點(diǎn)(rs7341475)在中國(guó)人群中是否與精神分裂癥相關(guān), 我們對(duì)一組來(lái)自中國(guó)云南省玉溪市的精神分裂癥病例——對(duì)照樣本(400位患者和400位正常人)進(jìn)行了遺傳關(guān)聯(lián)分析。

1 材料和方法

1.1 樣本

在云南省玉溪市第二人民醫(yī)院收集了400位精神分裂癥患者的血液, 包括227位女性和173位男性。這些患者經(jīng)過(guò)至少兩位精神病醫(yī)生鑒定診斷,并且符合 ICD-10標(biāo)準(zhǔn)?；加芯凭蕾嚲裾系K、頭部損傷、有吸毒經(jīng)歷或者癲癇等其他精神疾病的患者均被排除。同時(shí), 在云南當(dāng)?shù)厥占?00位正常人的血液, 包括208位女性和192位男性。這些正常人及其家屬都沒(méi)有精神分裂癥或者其他精神疾病的記錄。所有的樣本均為漢族, 所有的個(gè)體均提供了知情同意書(shū)。

1.2 基因分型

用標(biāo)準(zhǔn)的酚-氯仿的方法提取志愿者血樣的基因組 DNA, 提取的 DNA樣本隨機(jī)分布在PCR板里。通過(guò)聚合酶鏈?zhǔn)椒磻?yīng)(PCR)對(duì)含有目的位點(diǎn)的片段進(jìn)行擴(kuò)增。目的片段的正向引物是 5'-ACTGCAATAGAGGGGTACAGATT-3',反向引物是 5'-CTTCCTTGGTGCTTATACAAAG A-3', 反應(yīng)條件為預(yù)變性95 ℃, 5 min, 變性95 ℃, 30 s, 退火58 ℃, 30 s, 延伸72 ℃, 40 s, 共45個(gè)循環(huán),延伸72 ℃, 10 min。PCR反應(yīng)體系為25 μL, 包含20 ng基因組 DNA。用外切酶和蝦堿酶處理所得到的PCR產(chǎn)物, 以除去多余的dNTP和DNA單鏈堿基, 隨后在 rs7341475位點(diǎn) 5'端上游設(shè)計(jì)引物 5'-TTTTT TCCCTATTTTACAGATGAGAGAATTGAGACTCAAA-3'并進(jìn)行單堿基延伸反應(yīng)(SNaPShot)。SNaPShot的產(chǎn)物在 ABI3130分析儀上進(jìn)行基因分型, 隨后通過(guò)GeneMapper 4.0軟件自動(dòng)讀取基因分型結(jié)果, 并人工檢查校正。我們隨后隨機(jī)抽取了 50個(gè)個(gè)體進(jìn)行測(cè)序, 沒(méi)有發(fā)現(xiàn)分型錯(cuò)誤的個(gè)體。 基因分型成功率為100%。

1.3 統(tǒng)計(jì)分析

哈迪溫伯格平衡檢驗(yàn)采用 Haploview軟件完成 (Barrett et al, 2005)。對(duì)于病例-對(duì)照樣本遺傳分析, 用PLINK軟件進(jìn)行單核苷酸位點(diǎn)與疾病的相關(guān)性分析。同時(shí), 以性別作為協(xié)變量, 分別檢測(cè)了這個(gè)位點(diǎn)在男性和女性中與精神分裂癥的相關(guān)性(Purcell et al, 2007)。優(yōu)勢(shì)比(odds ratio)和95%的可信區(qū)間在網(wǎng)頁(yè)上計(jì)算(http://faculty.vassa r.edu/lowry/odds2x2.html)。

2 結(jié) 果

2.1 SNP特征和哈迪溫伯格平衡檢驗(yàn)

在遺傳分析的病例組和對(duì)照組中分別進(jìn)行的哈迪溫伯格平衡檢驗(yàn)結(jié)果顯示單核苷酸多態(tài)性位點(diǎn)未偏離哈迪溫伯格平衡。這個(gè)多態(tài)性位點(diǎn)的基因型頻率和基本信息見(jiàn)表1。

2.2 相關(guān)性分析

單位點(diǎn)分析結(jié)果見(jiàn)表 2。統(tǒng)計(jì)結(jié)果顯示, rs7341475位點(diǎn)中低頻基因型在精神分裂癥人群中的出現(xiàn)頻率與正常人群無(wú)顯著性差異（P=0.9273）,表明在本組病例樣本中, 該位點(diǎn)與精神分裂癥不相關(guān)。為了檢測(cè)是否存在性別特異的相關(guān)性, 我們將男性樣本和女性樣本分別進(jìn)行統(tǒng)計(jì), 分析發(fā)現(xiàn)無(wú)論男性還是女性, rs7341475都不與精神分裂癥相關(guān)。

表1 SNP rs7341475 的特征及等位基因頻率Tab. 1 Characteristics and allele frequencies of SNP rs7341475

表2 SNP rs7341475與精神分裂癥的相關(guān)性分析的P值Tab. 2 P values of the association tests of SNP rs7341475 with schizophrenia

3 討 論

RELN基因在胎兒或者成年人腦中表達(dá)(DeSilva et al, 1997), 主要參與神經(jīng)元遷移和定位(Tissir & Goffinet, 2003)。RELN基因與多種精神疾病發(fā)生相關(guān), 包括精神分裂癥、雙向情感障礙和老年癡呆癥等(Goes et al, 2009; Seripa et al, 2008; Shifman et al, 2008);RELN在這些精神疾病患者的腦中表達(dá)異常 (Fatemi et al, 2000; Guidotti et al, 2000)。這些數(shù)據(jù)表明,RELN在神經(jīng)發(fā)育系統(tǒng)起著很重要的作用, 但是對(duì)于它如何影響精神疾病的發(fā)生, 目前還沒(méi)有明確的解釋。

我們?cè)谥袊?guó)人群中檢測(cè)了rs7341475與精神分裂癥的相關(guān)性, 但是發(fā)現(xiàn)該位點(diǎn)不與精神分裂癥顯著相關(guān), 這表明在中國(guó)人群中 rs7341475可能并不是精神分裂癥的易感位點(diǎn)。值得注意的是, 雖然有報(bào)道 rs7341475與精神分裂癥相關(guān), 但是同樣也有很多研究小組發(fā)現(xiàn) rs7341475與精神分裂癥并不相關(guān) (Need et al, 2009)。在最近的一次薈萃分析(meta analysis)中, Ben-David & Shifman (2010)將所有研究過(guò)rs7341475的樣本綜合起來(lái)后發(fā)現(xiàn), rs7341475與精神分裂癥的相關(guān)顯著性并沒(méi)有最初GWAS發(fā)現(xiàn)的強(qiáng),并且如果除去最初的 GWAS研究, 發(fā)現(xiàn) rs7341475與精神分裂癥并不相關(guān)。這表明, 由于種族異質(zhì), 如遺傳結(jié)構(gòu)、環(huán)境因素、飲食和風(fēng)俗的差異, rs7341475可能只在某個(gè)種族(如猶太人)中與精神分裂癥相關(guān),而在其他民族中并不與精神分裂癥相關(guān)。當(dāng)然, 我們也不能排除 rs7341475并不是精神分裂癥易感位點(diǎn)的可能, 因?yàn)門(mén)ost et al(2010)研究發(fā)現(xiàn), rs7341475并不能影響 RELN基因在腦中的表達(dá), 同時(shí)也不能影響大腦的功能和結(jié)構(gòu)。

越來(lái)越多的研究表明,RELN是一個(gè)真實(shí)的精神分裂癥易感基因, 但是本研究表明, rs7341475可能并不是中國(guó)人群的致病多態(tài)性位點(diǎn)(不排除樣本量偏小的因素)。此外, 雖然rs7341475與精神分裂癥不相關(guān), 但有可能在RELN基因的其他位置上有精神分裂癥的易感位點(diǎn)。后續(xù)研究中, 我們將要加大樣本量和增加所研究的多態(tài)性位點(diǎn), 這樣可能會(huì)找到RELN基因的真正致病位點(diǎn)。

致謝：感謝為本研究的開(kāi)展提供DNA樣本的志愿者。感謝中國(guó)科學(xué)院昆明動(dòng)物研究所遺傳資源與進(jìn)化國(guó)家重點(diǎn)實(shí)驗(yàn)的張慧和李燕皎在實(shí)驗(yàn)方面的技術(shù)支持。

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Association ofRELNSNP rs7341475 with schizophrenia in the Chinese population

LIU Xing-Yan1, LI Ming2,3, YANG Shun-Ying1, SU Bing2,*, YIN Li-De1,*

(1.The Second People's Hospital of Yuxi City,Yuxi653101, China; 2.State Key Laboratory of Genetic Resources and Evolution,Kunming Institute of Zoology and Kunming Primate Research Center,the Chinese Academy of Sciences,Kunming650223,China; 3.Graduate School of Chinese Academy of Sciences, Beijing100101,China)

Schizophrenia is a common and complex psychiatric disorder. Significant evidence has suggested that genetic factors play pivotal roles in the etiology of schizophrenia. More than 100 schizophrenia candidate genes have been reported; however, many of them do not have satisfactory replications among different populations. Among these genes,RELNis thought to be associated with schizophrenia in many populations, suggesting it is a real risk gene for this disorder. Identified in the GWAS study, single nucleotide polymorphism (SNP) rs7341475, located in intron 4 ofRELN, has been successfully replicated in subsequent investigations, implying its potential contribution to schizophrenia susceptibility. To investigate the association of rs7341475 with schizophrenia in Chinese populations, a case-control association analysis was conducted with samples from Yuxi (400 cases and 400 controls) in southwestern China. The results do not indicate any association of rs7341475 with schizophrenia, which suggests it is not a risk SNP for schizophrenia in Han Chinese.

Schizophrenia;RELN; Single nucleotide polymorphism; Chinese population

Q987.2; Q593.2; R749.3

A

0254-5853-(2011)05-0499-05

10.3724/SP.J.1141.2011.05499

2011-03-29; 接受日期：2011-07-13

?通訊作者(Corresponding authors)，E-mail: sub@mail.kiz.ac.cn; yxyinlide@gmail.com

book=32,ebook=45