Kehoe P, Wavrant-De Vrieze F, Crook R, Wu W S, Holmans P, Fenton I, Spurlock G, Norton N, Williams H, Williams N, Lovestone S, Perez-Tur J, Hutton M, Chartier-Harlin M C, Shears S, Roehl K, Booth J, Van Voorst W, Ramic D, Williams J, Goate A, Hardy J, Owen M J
Neuropsychiatric Genetics Unit, Tenovus Building, University of Wales College of Medicine, Heath Park,Cardiff CF4 4XN, UK.
Hum Mol Genet. 1999 Feb;8(2):237-45. doi: 10.1093/hmg/8.2.237.
We have genotyped 292 affected sibling pairs (ASPs) with Alzheimer's disease (AD) according to NINCDS-ADRDA diagnostic criteria and with onset ages of >/=65 years using 237 microsatellite markers separated by an average distance of 16.3 cM. Data were analysed by SPLINK and MAPMAKER/SIBS on the whole sample of 292 ASPs and subsets of 162 ASPs where both members possessed an apolipoprotein E (APOE)straightepsilon4 allele and 63 pairs where neither possessed anstraightepsilon4 allele. Sixteen peaks with a multipoint lod score (MLS) >1 either in the whole sample, the straightepsilon4-positive or -negative subgroups were observed on chromosomes 1 (two peaks), 2, 5, 6, 9 (two peaks), 10 (two peaks), 12, 13, 14, 19, 21 and X (two peaks). Simulation studies revealed that these findings exceeded those expected by chance, although many are likely to be false positives. The highest lod scores on chromosomes 1 (MLS 2.67), 9 (MLS 2.38), 10 (MLS 2.27) and 19 (MLS 1.79) fulfilLander and Kruglyak's definition of 'suggestive' in that they would be expected to occur by chance once or less per genome scan. Several other peaks were only marginally less significant than this, in particular those on chromosomes 14 (MLS 2.16), 5 (MLS 2.00), 12, close to alpha2-macroglobulin (MLS 1.91), and 21, close to amyloid precursor protein (MLS 1.77). This is the largest genome scan to date in AD and shows for the first time that this is a genetically complex disorder involving several, perhaps many, genes in addition to APOE. Moreover, our data will be of interest to those hoping to identify positional candidate genes using information emerging from neurobiological studies of AD.
我们根据NINCDS-ADRDA诊断标准，对292对患有阿尔茨海默病（AD）且发病年龄≥65岁的患病同胞对（ASP）进行了基因分型，使用了237个平均间距为16.3厘摩的微卫星标记。通过SPLINK和MAPMAKER/SIBS对292对ASP的整个样本以及162对ASP的子集（其中两个成员都携带载脂蛋白E（APOE）ε4等位基因）和63对（其中两个成员都不携带ε4等位基因）进行了数据分析。在整个样本、ε4阳性或阴性亚组中，在1号染色体（两个峰值）、2号、5号、6号、9号染色体（两个峰值）、10号染色体（两个峰值）、12号、13号、14号、19号、21号和X染色体（两个峰值）上观察到16个多点对数优势分数（MLS）>1的峰值。模拟研究表明，这些发现超出了偶然预期的范围，尽管许多可能是假阳性。1号染色体上最高的对数优势分数（MLS 2.67）、9号染色体（MLS 2.38）、10号染色体（MLS 2.27）和19号染色体（MLS 1.79）符合兰德和克鲁格利亚克对“提示性”的定义，因为它们预计在每次全基因组扫描中偶然出现一次或更少。其他几个峰值的显著性仅略低于此，特别是14号染色体上的峰值（MLS 2.16）、5号染色体上的峰值（MLS 2.00）、靠近α2-巨球蛋白的12号染色体上的峰值（MLS 1.91）以及靠近淀粉样前体蛋白的21号染色体上的峰值（MLS 1.77）。这是迄今为止在AD中进行的最大规模的全基因组扫描，首次表明这是一种遗传复杂的疾病，除了APOE之外还涉及几个甚至可能许多基因。此外，我们的数据对于那些希望利用从AD的神经生物学研究中获得的信息来确定定位候选基因的人来说将是有意义的。
