Autosomal recessive causes likely in early-onset Alzheimer disease.
Autosomal recessive causes likely in early-onset Alzheimer disease.
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DOI：
10.1001/archneurol.2011.221
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发表时间：
2012-01
影响因子：
--
通讯作者：
Cutler, David J.
中科院分区：
文献类型：
--
作者：
Wingo, Thomas S.;Lah, James J.;Levey, Allan I.;Cutler, David J.
人们普遍认为，显性突变导致大多数早发性阿尔茨海默病（发病≤ 60岁，EOAD），但流行病学证据表明，显性突变可解释≤ 10%的所有EOAD病例。确定剩余约90%非常染色体显性EOAD病例的遗传贡献，并确定这些病例中可能的遗传机制。疾病的责任阈值模型被用来估计EOAD和迟发性AD（LOAD）的遗传度，使用父母-后代对之间的AD的一致性。在统一数据集（UDS）中确定了可能患有AD和详细父母病史的个体（n = 5，370），该数据集的参与者来自32个阿尔茨海默病中心。对于LOAD（n = 4，302），我们发现性别特异性亲子一致性范围约为10-30%，遗传率为69.8%（95% CI：64.6-75.0%），无论父母性别如何，两性的遗传率相等。对于EOAD（n = 702），我们发现亲子一致性≤ 10%，兄弟姐妹之间的一致性为21.6%。对于所有可能的EOAD患病率值，EOAD遗传率为92-100%。我们确认LOAD是一种高度多基因疾病。相比之下，EOAD的数据表明它几乎完全是一种基于遗传的疾病，并且在父母-子女对和兄弟姐妹之间观察到的一致性模式使我们拒绝EOAD是纯粹显性的、线粒体的、X连锁的或多基因疾病的假设。对该数据最可能的解释是，约90%的EOAD病例是由于常染色体隐性遗传所致。
There is a widespread belief that dominant mutations cause most cases of early-onset Alzheimer's Disease (onset ≤ 60 years, EOAD) yet epidemiologic evidence suggests they explain ≤ 10% of all EOAD cases. To determine the genetic contribution to the remaining ~90% of non-autosomal dominant EOAD cases and identify the likely mechanism of inheritance in those cases. A liability threshold model of disease was used to estimate heritability of EOAD and late-onset AD (LOAD) using concordance for AD among parent-offspring pairs. Individuals with probable AD and detailed parental history (n =5,370) were identified in the Uniform Dataset (UDS) whose participants were collected from 32 Alzheimer's Disease Centers. For LOAD (n = 4,302), we found sex-specific parent–offspring concordance that ranged from ~10-30% resulting in a heritability of 69.8% (95% CI: 64.6–75.0%) and equal heritability for both sexes regardless of parental gender. For EOAD (n = 702), we found that the parent–offspring concordance is ≤ 10% and concordance among siblings is 21.6%. EOAD heritability is 92–100% for all likely values of EOAD prevalence. We confirm LOAD is a highly polygenic disease. By contrast, the data for EOAD suggest it is an almost entirely genetically based disease, and the pattern of observed concordance for parent–offspring pairs and among siblings lead us to reject the hypotheses that EOAD is a purely dominant, mitochondrial, X-linked, or polygenic disorder. The most likely explanation of the data is that ~90% of EOAD cases are due to autosomal recessive causes.
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影响因子：
48
作者：
Rossor, Martin N.;Fox, Nick C.;Mummery, Catherine J.;Schott, Jonathan M.;Warren, Jason D.
通讯作者：
Warren, Jason D.
影响因子：
120.7
作者：
EVANS, DA;FUNKENSTEIN, H;TAYLOR, JO
通讯作者：
TAYLOR, JO
影响因子：
168.9
作者：
Raiha, I;Kaprio, J;Sourander, L
通讯作者：
Sourander, L
影响因子：
9.8
作者：
Daw, EW;Payami, H;Wijsman, EM
通讯作者：
Wijsman, EM
影响因子：
--
作者：
Evans, DA;Bennett, DA;Schneider, J
通讯作者：
Schneider, J