Naj Adam C, Jun Gyungah, Reitz Christiane, Kunkle Brian W, Perry William, Park Yo Son, Beecham Gary W, Rajbhandary Ruchita A, Hamilton-Nelson Kara L, Wang Li-San, Kauwe John S K, Huentelman Matthew J, Myers Amanda J, Bird Thomas D, Boeve Bradley F, Baldwin Clinton T, Jarvik Gail P, Crane Paul K, Rogaeva Ekaterina, Barmada M Michael, Demirci F Yesim, Cruchaga Carlos, Kramer Patricia L, Ertekin-Taner Nilufer, Hardy John, Graff-Radford Neill R, Green Robert C, Larson Eric B, St George-Hyslop Peter H, Buxbaum Joseph D, Evans Denis A, Schneider Julie A, Lunetta Kathryn L, Kamboh M Ilyas, Saykin Andrew J, Reiman Eric M, De Jager Philip L, Bennett David A, Morris John C, Montine Thomas J, Goate Alison M, Blacker Deborah, Tsuang Debby W, Hakonarson Hakon, Kukull Walter A, Foroud Tatiana M, Martin Eden R, Haines Jonathan L, Mayeux Richard P, Farrer Lindsay A, Schellenberg Gerard D, Pericak-Vance Margaret A, Albert Marilyn S, Albin Roger L, Apostolova Liana G, Arnold Steven E, Barber Robert, Barnes Lisa L, Beach Thomas G, Becker James T, Beekly Duane, Bigio Eileen H, Bowen James D, Boxer Adam, Burke James R, Cairns Nigel J, Cantwell Laura B, Cao Chuanhai, Carlson Chris S, Carney Regina M, Carrasquillo Minerva M, Carroll Steven L, Chui Helena C, Clark David G, Corneveaux Jason, Cribbs David H, Crocco Elizabeth A, DeCarli Charles, DeKosky Steven T, Dick Malcolm, Dickson Dennis W, Duara Ranjan, Faber Kelley M, Fallon Kenneth B, Farlow Martin R, Ferris Steven, Frosch Matthew P, Galasko Douglas R, Ganguli Mary, Gearing Marla, Geschwind Daniel H, Ghetti Bernardino, Gilbert John R, Glass Jonathan D, Growdon John H, Hamilton Ronald L, Harrell Lindy E, Head Elizabeth, Honig Lawrence S, Hulette Christine M, Hyman Bradley T, Jicha Gregory A, Jin Lee-Way, Karydas Anna, Kaye Jeffrey A, Kim Ronald, Koo Edward H, Kowall Neil W, Kramer Joel H, LaFerla Frank M, Lah James J, Leverenz James B, Levey Allan I, Li Ge, Lieberman Andrew P, Lin Chiao-Feng, Lopez Oscar L, Lyketsos Constantine G, Mack Wendy J, Martiniuk Frank, Mash Deborah C, Masliah Eliezer, McCormick Wayne C, McCurry Susan M, McDavid Andrew N, McKee Ann C, Mesulam Marsel, Miller Bruce L, Miller Carol A, Miller Joshua W, Murrell Jill R, Olichney John M, Pankratz Vernon S, Parisi Joseph E, Paulson Henry L, Peskind Elaine, Petersen Ronald C, Pierce Aimee, Poon Wayne W, Potter Huntington, Quinn Joseph F, Raj Ashok, Raskind Murray, Reisberg Barry, Ringman John M, Roberson Erik D, Rosen Howard J, Rosenberg Roger N, Sano Mary, Schneider Lon S, Seeley William W, Smith Amanda G, Sonnen Joshua A, Spina Salvatore, Stern Robert A, Tanzi Rudolph E, Thornton-Wells Tricia A, Trojanowski John Q, Troncoso Juan C, Valladares Otto, Van Deerlin Vivianna M, Van Eldik Linda J, Vardarajan Badri N, Vinters Harry V, Vonsattel Jean Paul, Weintraub Sandra, Welsh-Bohmer Kathleen A, Williamson Jennifer, Wishnek Sarah, Woltjer Randall L, Wright Clinton B, Younkin Steven G, Yu Chang-En, Yu Lei
Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia.
Genetics Program, Department of Medicine, Boston University, Boston, Massachusetts4Department of Biostatistics, Boston University, Boston, Massachusetts5Department of Ophthalmology, Boston University, Boston, Massachusetts.
JAMA Neurol. 2014 Nov;71(11):1394-404. doi: 10.1001/jamaneurol.2014.1491.
Because APOE locus variants contribute to risk of late-onset Alzheimer disease (LOAD) and to differences in age at onset (AAO), it is important to know whether other established LOAD risk loci also affect AAO in affected participants.
To investigate the effects of known Alzheimer disease risk loci in modifying AAO and to estimate their cumulative effect on AAO variation using data from genome-wide association studies in the Alzheimer Disease Genetics Consortium.
DESIGN, SETTING, AND PARTICIPANTS: The Alzheimer Disease Genetics Consortium comprises 14 case-control, prospective, and family-based data sets with data on 9162 participants of white race/ethnicity with Alzheimer disease occurring after age 60 years who also had complete AAO information, gathered between 1989 and 2011 at multiple sites by participating studies. Data on genotyped or imputed single-nucleotide polymorphisms most significantly associated with risk at 10 confirmed LOAD loci were examined in linear modeling of AAO, and individual data set results were combined using a random-effects, inverse variance-weighted meta-analysis approach to determine whether they contribute to variation in AAO. Aggregate effects of all risk loci on AAO were examined in a burden analysis using genotype scores weighted by risk effect sizes.
Age at disease onset abstracted from medical records among participants with LOAD diagnosed per standard criteria.
Analysis confirmed the association of APOE with earlier AAO (P = 3.3 × 10(-96)), with associations in CR1 (rs6701713, P = 7.2 × 10(-4)), BIN1 (rs7561528, P = 4.8 × 10(-4)), and PICALM (rs561655, P = 2.2 × 10(-3)) reaching statistical significance (P < .005). Risk alleles individually reduced AAO by 3 to 6 months. Burden analyses demonstrated that APOE contributes to 3.7% of the variation in AAO (R(2) = 0.256) over baseline (R(2) = 0.221), whereas the other 9 loci together contribute to 2.2% of the variation (R(2) = 0.242).
We confirmed an association of APOE (OMIM 107741) variants with AAO among affected participants with LOAD and observed novel associations of CR1 (OMIM 120620), BIN1 (OMIM 601248), and PICALM (OMIM 603025) with AAO. In contrast to earlier hypothetical modeling, we show that the combined effects of Alzheimer disease risk variants on AAO are on the scale of, but do not exceed, the APOE effect. While the aggregate effects of risk loci on AAO may be significant, additional genetic contributions to AAO are individually likely to be small.
由于载脂蛋白E（APOE）基因座变异会增加晚发型阿尔茨海默病（LOAD）的风险并导致发病年龄（AAO）存在差异，因此了解其他已确定的LOAD风险基因座是否也会影响受影响参与者的AAO非常重要。
利用阿尔茨海默病遗传学联盟全基因组关联研究的数据，调查已知阿尔茨海默病风险基因座对改变AAO的影响，并估计它们对AAO变异的累积效应。
设计、设置和参与者：阿尔茨海默病遗传学联盟包括14个病例对照、前瞻性和基于家庭的数据集，数据来自9162名60岁以后发生阿尔茨海默病且有完整AAO信息的白人种族/族裔参与者，这些数据由参与研究于1989年至2011年在多个地点收集。在AAO的线性模型中检查了与10个已确认的LOAD基因座风险最显著相关的基因分型或推算单核苷酸多态性数据，并使用随机效应、逆方差加权荟萃分析方法合并个体数据集结果，以确定它们是否导致AAO变异。使用按风险效应大小加权的基因型评分，在负担分析中检查所有风险基因座对AAO的总体效应。
根据标准标准诊断为LOAD的参与者的病历中提取的疾病发病年龄。
分析证实APOE与较早的AAO相关（P = 3.3×10⁻⁹⁶），补体受体1（CR1，rs6701713，P = 7.2×10⁻⁴）、桥联整合因子1（BIN1，rs7561528，P = 4.8×10⁻⁴）和磷脂酰肌醇结合网格蛋白组装蛋白（PICALM，rs561655，P = 2.2×10⁻³）的关联达到统计学显著性（P < 0.005）。风险等位基因分别使AAO降低3至6个月。负担分析表明，APOE导致AAO变异的3.7%（R² = 0.256）超过基线（R² = 0.221），而其他9个基因座共同导致2.2%的变异（R² = 0.242）。
我们证实了APOE（OMIM 107741）变异与LOAD受影响参与者的AAO相关，并观察到CR1（OMIM 120620）、BIN1（OMIM 601248）和PICALM（OMIM 603025）与AAO有新的关联。与早期的假设模型相反，我们表明阿尔茨海默病风险变异对AAO的综合影响与APOE的影响相当，但不超过APOE的影响。虽然风险基因座对AAO的总体影响可能很大，但对AAO的额外遗传贡献可能个体较小。
