Dementia revealed: novel chromosome 6 locus for late-onset Alzheimer disease provides genetic evidence for folate-pathway abnormalities.
Dementia revealed: novel chromosome 6 locus for late-onset Alzheimer disease provides genetic evidence for folate-pathway abnormalities.
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DOI：
10.1371/journal.pgen.1001130
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发表时间：
2010-09-23
期刊：
影响因子：
4.5
通讯作者：
Pericak-Vance MA
中科院分区：
文献类型：
--
作者：
Naj AC;Beecham GW;Martin ER;Gallins PJ;Powell EH;Konidari I;Whitehead PL;Cai G;Haroutunian V;Scott WK;Vance JM;Slifer MA;Gwirtsman HE;Gilbert JR;Haines JL;Buxbaum JD;Pericak-Vance MA
晚发性阿尔茨海默病（LOAD）的全基因组关联研究（GWAS）一直观察到与APOE多态性相关的强有力证据。然而，直到最近，在其他几个具有统计学显著关联的基因座上的变异在研究中重复。本研究结合了来自先前报道的492例LOAD病例和496例对照的GWAS以及来自439例LOAD病例和608例对照的483，399个单核苷酸多态性（SNP）的数据，以加强识别新的遗传关联信号的能力。在另外1,338例病例和2,003例对照中，超过实验范围内显著性阈值（）的关联被复制。正如预期的那样，这些分析明确证实了APOE的风险效应（rs2075650，）。此外，MTHFD1L基因（编码亚甲基四氢叶酸脱氢酶（NADP+依赖性）1样蛋白）染色体6q25.1 151.2 Mb处的SNP rs11754661与LOAD显著相关（Bonferroni校正P = 0.022）。 随后对rs11754661的高连锁不平衡（）中的SNP进行基因分型，发现多个SNP之间存在统计学显著相关性（rs803424，P = 0.016; rs2073067，P = 0.03; rs2072064，P = 0.035），降低了因基因分型错误导致相关的可能性。 在复制病例-对照组中，我们观察到rs11754661的关联与先前的关联方向相同，P = 0.002（在发现集和复制集的联合分析中），在几个相邻的SNP（rs17349743，P = 0.005; rs803422，P = 0.004）中具有相似的统计学显著性。 总之，我们观察到并复制了一种新的统计学显着的关联MTHFD1L，一个基因参与四氢叶酸合成途径。这一发现值得注意，因为MTHFD1L可能在从同型半胱氨酸生成甲硫氨酸中发挥作用并影响同型半胱氨酸相关途径，并且同型半胱氨酸水平是LOAD发展的重要风险因素。寻找影响晚发性阿尔茨海默病（LOAD）的基因组遗传变异的研究在识别APOE以外的基因方面几乎没有成功。在这里，我们使用一组扩展的AD病例和对照，以提高我们检测驱动LOAD风险的遗传变异的能力。在931例病例和1，104例对照的发现数据集中分析了基因组中的483，399个遗传变异，我们发现除了高度复制的19号染色体APOE关联外，MTHFD1L基因中的6号染色体上的标记rs11754661也有很强的关联。我们在这些相同的病例和对照中对6号染色体上的相邻变异进行了基因分型，发现这些变异也与LOAD相关。我们在我们实验室和公开数据集的病例和对照组合数据集中复制了与rs11754661和MTHFD1L中其他SNP的关联。这一发现很重要，因为已知该基因参与影响同型半胱氨酸水平的生物学途径，同型半胱氨酸是AD的重要风险因素。
Genome-wide association studies (GWAS) of late-onset Alzheimer disease (LOAD) have consistently observed strong evidence of association with polymorphisms in APOE. However, until recently, variants at few other loci with statistically significant associations have replicated across studies. The present study combines data on 483,399 single nucleotide polymorphisms (SNPs) from a previously reported GWAS of 492 LOAD cases and 496 controls and from an independent set of 439 LOAD cases and 608 controls to strengthen power to identify novel genetic association signals. Associations exceeding the experiment-wide significance threshold () were replicated in an additional 1,338 cases and 2,003 controls. As expected, these analyses unequivocally confirmed APOE's risk effect (rs2075650, ). Additionally, the SNP rs11754661 at 151.2 Mb of chromosome 6q25.1 in the gene MTHFD1L (which encodes the methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1-like protein) was significantly associated with LOAD (; Bonferroni-corrected P = 0.022). Subsequent genotyping of SNPs in high linkage disequilibrium () with rs11754661 identified statistically significant associations in multiple SNPs (rs803424, P = 0.016; rs2073067, P = 0.03; rs2072064, P = 0.035), reducing the likelihood of association due to genotyping error. In the replication case-control set, we observed an association of rs11754661 in the same direction as the previous association at P = 0.002 ( in combined analysis of discovery and replication sets), with associations of similar statistical significance at several adjacent SNPs (rs17349743, P = 0.005; rs803422, P = 0.004). In summary, we observed and replicated a novel statistically significant association in MTHFD1L, a gene involved in the tetrahydrofolate synthesis pathway. This finding is noteworthy, as MTHFD1L may play a role in the generation of methionine from homocysteine and influence homocysteine-related pathways and as levels of homocysteine are a significant risk factor for LOAD development. Studies looking for genetic variants across the genome that affect late-onset Alzheimer disease (LOAD) have had little success identifying genes other than APOE. Here, we use an expanded set of AD cases and controls to improve our power to detect genetic variants driving LOAD risk. Analyzing 483,399 genetic variants across the genome in a discovery dataset of 931 cases and 1,104 controls, we found a strong association to the marker rs11754661 on chromosome 6 in the gene MTHFD1L, in addition to the highly replicated chromosome 19 APOE association. We genotyped adjacent variants on chromosome 6 in these same cases and controls and found these variants were also associated with LOAD. We replicated the association with rs11754661 and additional SNPs in MTHFD1L in a combined dataset of cases and controls from our laboratory and from publicly available datasets. This finding is important because the gene is known to be involved in biological pathways influencing levels of homocysteine, a significant risk factor for AD.
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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：
2.7
作者：
Abraham R;Moskvina V;Sims R;Hollingworth P;Morgan A;Georgieva L;Dowzell K;Cichon S;Hillmer AM;O'Donovan MC;Williams J;Owen MJ;Kirov G
通讯作者：
Kirov G
影响因子：
--
作者：
Haroutunian, V;Perl, DP;Mohs, RC
通讯作者：
Mohs, RC
影响因子：
3
作者：
de Luis, DA;Fernandez, N;Romero, E
通讯作者：
Romero, E
影响因子：
3.5
作者：
Blacker, D;Bertram, L;Tanzi, RE
通讯作者：
Tanzi, RE