Scott William K, Hauser Elizabeth R, Schmechel Donald E, Welsh-Bohmer Kathleen A, Small Gary W, Roses Allen D, Saunders Ann M, Gilbert John R, Vance Jeffery M, Haines Jonathan L, Pericak-Vance Margaret A
Department of Medicine, Duke University Medical Center, and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University, Durham, NC 27710, USA.
Am J Hum Genet. 2003 Nov;73(5):1041-51. doi: 10.1086/379083. Epub 2003 Oct 16.
Alzheimer disease (AD) is a complex disorder characterized by a wide range, within and between families, of ages at onset of symptoms. Consideration of age at onset as a covariate in genetic-linkage studies may reduce genetic heterogeneity and increase statistical power. Ordered-subsets analysis includes continuous covariates in linkage analysis by rank ordering families by a covariate and summing LOD scores to find a subset giving a significantly increased LOD score relative to the overall sample. We have analyzed data from 336 markers in 437 multiplex (>/=2 sampled individuals with AD) families included in a recent genomic screen for AD loci. To identify genetic heterogeneity by age at onset, families were ordered by increasing and decreasing mean and minimum ages at onset. Chromosomewide significance of increases in the LOD score in subsets relative to the overall sample was assessed by permutation. A statistically significant increase in the nonparametric multipoint LOD score was observed on chromosome 2q34, with a peak LOD score of 3.2 at D2S2944 (P=.008) in 31 families with a minimum age at onset between 50 and 60 years. The LOD score in the chromosome 9p region previously linked to AD increased to 4.6 at D9S741 (P=.01) in 334 families with minimum age at onset between 60 and 75 years. LOD scores were also significantly increased on chromosome 15q22: a peak LOD score of 2.8 (P=.0004) was detected at D15S1507 (60 cM) in 38 families with minimum age at onset >/=79 years, and a peak LOD score of 3.1 (P=.0006) was obtained at D15S153 (62 cM) in 43 families with mean age at onset >80 years. Thirty-one families were contained in both 15q22 subsets, indicating that these results are likely detecting the same locus. There is little overlap in these subsets, underscoring the utility of age at onset as a marker of genetic heterogeneity. These results indicate that linkage to chromosome 9p is strongest in late-onset AD and that regions on chromosome 2q34 and 15q22 are linked to early-onset AD and very-late-onset AD, respectively.
阿尔茨海默病（AD）是一种复杂的疾病，其症状发作年龄在家族内部和家族之间存在广泛差异。在基因连锁研究中将发病年龄作为协变量考虑，可能会减少基因异质性并提高统计效力。有序子集分析通过按协变量对家族进行排序并对对数优势（LOD）得分求和，在连锁分析中纳入连续协变量，以找到相对于总体样本LOD得分显著增加的子集。我们分析了近期AD基因座基因组筛查中纳入的437个多重（≥2个患AD的抽样个体）家族中336个标记的数据。为了按发病年龄识别基因异质性，家族按发病平均年龄和最小年龄的升序和降序排列。通过置换评估子集中LOD得分相对于总体样本增加的全染色体显著性。在2q34染色体上观察到非参数多点LOD得分有统计学显著增加，在31个发病最小年龄在50至60岁之间的家族中，D2S2944处的峰值LOD得分为3.2（P = 0.008）。先前与AD连锁的9p染色体区域的LOD得分在334个发病最小年龄在60至75岁之间的家族中，在D9S741处增加到4.6（P = 0.01）。15q22染色体上的LOD得分也显著增加：在38个发病最小年龄≥79岁的家族中，D15S1507（60厘摩）处检测到峰值LOD得分为2.8（P = 0.0004），在43个发病平均年龄>80岁的家族中，D15S153（62厘摩）处获得峰值LOD得分为3.1（P = 0.0006）。两个15q22子集中都包含31个家族，表明这些结果可能检测到了相同的基因座。这些子集之间几乎没有重叠，突出了发病年龄作为基因异质性标记的效用。这些结果表明，与9p染色体的连锁在晚发性AD中最强，而2q34和15q22染色体区域分别与早发性AD和极晚发性AD连锁。
