Dickson M Ryan, Li Jian, Wiener Howard W, Perry Rodney T, Blacker Deborah, Bassett Susan S, Go Rodney C P
Department of Epidemiology and International Health, The University of Alabama at Birmingham, Birmingham, Alabama 35294-0001, USA.
Am J Med Genet B Neuropsychiatr Genet. 2008 Sep 5;147B(6):784-92. doi: 10.1002/ajmg.b.30689.
We performed linkage analysis for age at onset (AAO) in the total Alzheimer's disease (AD) NIMH sample (N = 437 families). Families were subset as late-onset (320 families, AAO > or = 65) and early/mixed (117 families, at least 1 member with 50 < AAO < 65). Treating AAO as a censored trait, we obtained the gender and APOE adjusted residuals in a parametric survival model and analyzed the residuals as the quantitative trait (QT) in variance-component linkage analysis. For comparison, AAO-age at exam (AAE) was analyzed as the QT adjusting for affection status, gender, and APOE. Heritabilities for residual and AAO-AAE outcomes were 66.3% and 74.0%, respectively for the total sample, 56.0% and 57.0% in the late-onset sample, and 33.0% for both models in the early/mixed sample. The residual model yielded the largest peaks on chromosome 1 with LOD = 2.0 at 190 cM in the total set, LOD = 1.7 at 116 cM on chromosome 3 in the early/mixed subset, and LOD = 1.4 at 71 and 86 cM, respectively, on chromosome 6 in the late-onset subset. For the AAO-AAE outcome model the largest peaks were identified on chromosome 1 at 137 cM (LOD = 2.8) and chromosome 6 at 69 cM (LOD = 2.3) and 86 cM (LOD = 2.2) all in the late-onset subset. Additional peaks with LOD > or = 1 were identified on chromosomes 1, 2, 3, 6, 8, 9, 10, and 12 for the total sample and each subset. Results replicate previous findings, but identify additional suggestive peaks indicating the genetics of AAO in AD is complex with many chromosomal regions potentially containing modifying genes.
我们对国立精神卫生研究所（NIMH）的全部阿尔茨海默病（AD）样本（N = 437个家庭）的发病年龄（AAO）进行了连锁分析。家庭被分为晚发性（320个家庭，AAO≥65岁）和早发性/混合型（117个家庭，至少有一名成员的AAO在50＜AAO＜65岁之间）。将AAO视为截尾性状，我们在参数生存模型中获得了性别和载脂蛋白E（APOE）调整后的残差，并在方差成分连锁分析中将残差作为数量性状（QT）进行分析。为作比较，将检查时的年龄（AAE）作为QT进行分析，并对情感状态、性别和APOE进行调整。总样本中残差和AAO - AAE结果的遗传度分别为66.3%和74.0%，晚发性样本中分别为56.0%和57.0%，早发性/混合型样本中两种模型均为33.0%。残差模型在全集中于1号染色体190厘摩（cM）处产生最大峰，LOD值为2.0；在早发性/混合型子集中于3号染色体116 cM处产生最大峰，LOD值为1.7；在晚发性子集中于6号染色体71 cM和86 cM处分别产生最大峰，LOD值为1.4。对于AAO - AAE结果模型，最大峰出现在晚发性子集中的1号染色体137 cM处（LOD = 2.8）以及6号染色体69 cM处（LOD = 2.3）和86 cM处（LOD = 2.2）。在总样本和每个子集中，在1、2、3、6、8、9、10和12号染色体上还发现了LOD≥1的其他峰。结果重复了先前的发现，但识别出了其他提示性峰，表明AD中AAO的遗传学很复杂，许多染色体区域可能包含修饰基因。
