Pericak-Vance M A, Bass M P, Yamaoka L H, Gaskell P C, Scott W K, Terwedow H A, Menold M M, Conneally P M, Small G W, Vance J M, Saunders A M, Roses A D, Haines J L
Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
JAMA. 1997 Oct 15;278(15):1237-41.
Four genetic loci have been identified as contributing to Alzheimer disease (AD), including the amyloid precursor protein gene, the presenilin 1 gene, the presenilin 2 gene, and the apolipoprotein E gene, but do not account for all the genetic risk for AD.
To identify additional genetic risk factors for late-onset AD.
A complete genomic screen was performed (N=280 markers). Critical values for chromosomal regional follow-up were a P value of .05 or less for affected relative pair analysis or sibpair analysis, a parametric lod score of 1.0 or greater, or both. Regional follow-up included analysis of additional markers and a second data set.
Clinic populations in the continental United States.
From a series of multiplex families affected with late-onset (> or =60 years) AD ascertained during the last 14 years (National Insititute of Neurological Disorders and Stroke-Alzheimer's Disease and Related Disorders Association diagnostic criteria) and for which DNA has been obtained, a subset of 16 families (135 total family members, 52 of whom were patients with AD) was used for the genomic screen. A second subset of 38 families (216 total family members, 89 of whom were patients with AD) was used for the follow-up analysis.
Linkage analysis results generated using both genetic model-dependent (lod score) and model-independent methods.
Fifteen chromosomal regions warranted initial follow-up. Follow-up analyses revealed 4 regions of continued interest on chromosomes 4, 6, 12, and 20, with the strongest results observed forchromosome 12. Peak 2-point affecteds-only lod scores (n=54) were 1.3, 1.6, 2.7, and 2.2 and affected relative pairs P values (n=54) were .04, .03, .14, and .04 for D12S373, D12S1057, D12S1042, and D12S390, respectively. Sibpair analysis (n=54) resulted in maximum lod scores (MLSs) of 1.5, 2.6, 3.2, and 2.3 for these markers, with a peak multipoint MLS of 3.5. A priori stratification by APOE genotype identified 27 families that had at least 1 member with AD whose genotype did not contain an APOE*4 allele. Analysis of these 27 families resulted in MLSs of 1.0, 2.4, 3.7, and 3.3 and a peak multipoint MLS of 3.9.
A complete genomic screen in families affected with late-onset AD identified 4 regions of interest after follow-up. Chromosome 12 gave the strongest and most consistent results with a peak multipoint MLS of 3.5, suggesting that this region contains a new susceptibility gene for AD. Additional analyses are necessary to identify the chromosome 12 susceptibility gene for AD and to follow up the regions of interest on chromosomes 4, 6, and 20.
已确定有四个基因位点与阿尔茨海默病（AD）相关，包括淀粉样前体蛋白基因、早老素1基因、早老素2基因和载脂蛋白E基因，但它们并不能解释AD所有的遗传风险。
确定晚发性AD的其他遗传风险因素。
进行了一次全基因组筛查（N = 280个标记）。染色体区域后续研究的临界值为：受累亲属对分析或同胞对分析的P值为0.05或更低，参数化对数优势分数为1.0或更高，或两者兼有。区域后续研究包括对额外标记的分析和第二个数据集。
美国大陆的临床人群。
从过去14年中确诊的一系列晚发性（≥60岁）AD的多重家庭中选取（根据美国国立神经疾病和中风研究所-阿尔茨海默病及相关疾病协会的诊断标准），且已获取其DNA，其中16个家庭（共135名家庭成员，其中52名是AD患者）的子集用于基因组筛查。38个家庭（共216名家庭成员，其中89名是AD患者）的第二个子集用于后续分析。
使用依赖遗传模型（对数优势分数）和不依赖模型的方法生成的连锁分析结果。
15个染色体区域需要进行初步后续研究。后续分析显示，4号、6号、12号和20号染色体上有4个区域仍值得关注，其中12号染色体的结果最为显著。对于D12S373、D12S1057、D12S1042和D12S390，仅受累个体的两点对数优势分数峰值（n = 54）分别为1.3、1.6、2.7和2.2，受累亲属对P值（n = 54）分别为0.04、0.03、0.14和0.04。同胞对分析（n = 54）中，这些标记的最大对数优势分数（MLS）分别为1.5、2.6、3.2和2.3，多点MLS峰值为3.5。根据APOE基因型进行的先验分层确定了27个家庭，这些家庭中至少有1名AD患者，其基因型不包含APOE*4等位基因。对这27个家庭的分析得出MLS分别为1.0、2.4、3.7和3.3，多点MLS峰值为3.9。
对晚发性AD家庭进行的全基因组筛查在后续研究后确定了4个感兴趣的区域。12号染色体给出了最强且最一致的结果，多点MLS峰值为3.5，表明该区域包含一个新的AD易感基因。需要进行更多分析以确定12号染色体上的AD易感基因，并对4号、6号和20号染色体上的感兴趣区域进行后续研究。
