An intronic VNTR affects splicing of ABCA7 and increases risk of Alzheimer's disease.
An intronic VNTR affects splicing of ABCA7 and increases risk of Alzheimer's disease.
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DOI：
10.1007/s00401-018-1841-z
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发表时间：
2018-06
影响因子：
12.7
通讯作者：
BELNEU Consortium
中科院分区：
文献类型：
--
作者：
De Roeck A;Duchateau L;Van Dongen J;Cacace R;Bjerke M;Van den Bossche T;Cras P;Vandenberghe R;De Deyn PP;Engelborghs S;Van Broeckhoven C;Sleegers K;BELNEU Consortium
导致atp结合盒亚家族A成员7 （ABCA7）过早终止密码子的突变是阿尔茨海默病（AD）的高渗透危险因素。然而，其他遗传变异对ABCA7及其下游功能机制的影响尚不清楚。为了解决这一知识差距，我们研究了比利时1529名AD患者和对照个体的ABCA7串联重复区域，并确定了一个含子可变数串联重复（VNTR）。我们观察到VNTR长度与ABCA7位点的AD全基因组相关信号之间存在很强的相关性。扩展的VNTR等位基因在AD患者中高度富集[优势比= 4.5(1.3-24.2)]，且VNTR长度与脑脊液中淀粉样蛋白β1-42和ABCA7表达呈负相关。此外，我们还发现了三个新的ABCA7选择性剪接事件。其中一种异构体是通过外显子19的跳跃形成的，缺乏ABCA7的第一个核苷酸结合域，在脑组织中含量丰富。我们观察到外显子19跳变与VNTR长度密切相关。我们的研究结果强调了在复杂疾病中研究重复DNA的重要性，并扩大了ABCA7基因和转录物变异对AD的贡献。本文的在线版本（10.1007/s00401-018-1841-z）包含补充资料，仅供授权用户使用。
Mutations leading to premature termination codons in ATP-Binding Cassette Subfamily A Member 7 (ABCA7) are high penetrant risk factors of Alzheimer’s disease (AD). The influence of other genetic variants in ABCA7 and downstream functional mechanisms, however, is poorly understood. To address this knowledge gap, we investigated tandem repetitive regions in ABCA7 in a Belgian cohort of 1529 AD patients and control individuals and identified an intronic variable number tandem repeat (VNTR). We observed strong association between VNTR length and a genome-wide associated signal for AD in the ABCA7 locus. Expanded VNTR alleles were highly enriched in AD patients [odds ratio = 4.5 (1.3–24.2)], and VNTR length inversely correlated with amyloid β1–42 in cerebrospinal fluid and ABCA7 expression. In addition, we identified three novel ABCA7 alternative splicing events. One isoform in particular—which is formed through exon 19 skipping—lacks the first nucleotide binding domain of ABCA7 and is abundant in brain tissue. We observed a tight correlation between exon 19 skipping and VNTR length. Our findings underline the importance of studying repetitive DNA in complex disorders and expand the contribution of genetic and transcript variation in ABCA7 to AD. The online version of this article (10.1007/s00401-018-1841-z) contains supplementary material, which is available to authorized users.
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DOI：
10.1016/j.jalz.2011.03.005
发表时间：
2011-05
期刊：
Alzheimer's & dementia : the journal of the Alzheimer's Association
影响因子：
--
作者：
McKhann GM;Knopman DS;Chertkow H;Hyman BT;Jack CR Jr;Kawas CH;Klunk WE;Koroshetz WJ;Manly JJ;Mayeux R;Mohs RC;Morris JC;Rossor MN;Scheltens P;Carrillo MC;Thies B;Weintraub S;Phelps CH
通讯作者：
Phelps CH
影响因子：
30.8
作者：
Harold, Denise;Abraham, Richard;Hollingworth, Paul;Sims, Rebecca;Gerrish, Amy;Hamshere, Marian L.;Pahwa, Jaspreet Singh;Moskvina, Valentina;Dowzell, Kimberley;Williams, Amy;Jones, Nicola;Thomas, Charlene;Stretton, Alexandra;Morgan, Angharad R.;Lovestone, Simon;Powell, John;Proitsi, Petroula;Lupton, Michelle K.;Brayne, Carol;Rubinsztein, David C.;Gill, Michael;Lawlor, Brian;Lynch, Aoibhinn;Morgan, Kevin;Brown, Kristelle S.;Passmore, Peter A.;Craig, David;McGuinness, Bernadette;Todd, Stephen;Holmes, Clive;Mann, David;Smith, A. David;Love, Seth;Kehoe, Patrick G.;Hardy, John;Mead, Simon;Fox, Nick;Rossor, Martin;Collinge, John;Maier, Wolfgang;Jessen, Frank;Schuermann, Britta;van den Bussche, Hendrik;Heuser, Isabella;Kornhuber, Johannes;Wiltfang, Jens;Dichgans, Martin;Froelich, Lutz;Hampel, Harald;Huell, Michael;Rujescu, Dan;Goate, Alison M.;Kauwe, John S. K.;Cruchaga, Carlos;Nowotny, Petra;Morris, John C.;Mayo, Kevin;Sleegers, Kristel;Bettens, Karolien;Engelborghs, Sebastiaan;De Deyn, Peter P.;Van Broeckhoven, Christine;Livingston, Gill;Bass, Nicholas J.;Gurling, Hugh;McQuillin, Andrew;Gwilliam, Rhian;Deloukas, Panagiotis;Al-Chalabi, Ammar;Shaw, Christopher E.;Tsolaki, Magda;Singleton, Andrew B.;Guerreiro, Rita;Muehleisen, Thomas W.;Noethen, Markus M.;Moebus, Susanne;Joeckel, Karl-Heinz;Klopp, Norman;Wichmann, H-Erich;Carrasquillo, Minerva M.;Pankratz, V. Shane;Younkin, Steven G.;Holmans, Peter A.;O'Donovan, Michael;Owen, Michael J.;Williams, Julie
通讯作者：
Williams, Julie
影响因子：
48
作者：
Cuyvers, Elise;De Roeck, Arne;Sleegers, Kristel
通讯作者：
Sleegers, Kristel
影响因子：
14.9
作者：
Mathelier A;Fornes O;Arenillas DJ;Chen CY;Denay G;Lee J;Shi W;Shyr C;Tan G;Worsley-Hunt R;Zhang AW;Parcy F;Lenhard B;Sandelin A;Wasserman WW
通讯作者：
Wasserman WW
DOI：
10.1212/nxg.0000000000000079
发表时间：
2016-06
期刊：
Neurology. Genetics
影响因子：
--
作者：
Cukier HN;Kunkle BW;Vardarajan BN;Rolati S;Hamilton-Nelson KL;Kohli MA;Whitehead PL;Dombroski BA;Van Booven D;Lang R;Dykxhoorn DM;Farrer LA;Cuccaro ML;Vance JM;Gilbert JR;Beecham GW;Martin ER;Carney RM;Mayeux R;Schellenberg GD;Byrd GS;Haines JL;Pericak-Vance MA;Alzheimer's Disease Genetics Consortium
通讯作者：
Alzheimer's Disease Genetics Consortium