Cardno A G, Holmans P A, Rees M I, Jones L A, McCarthy G M, Hamshere M L, Williams N M, Norton N, Williams H J, Fenton I, Murphy K C, Sanders R D, Gray M Y, O'Donovan M C, McGuffin P, Owen M J
Department of Psychological Medicine, University of Wales College of Medicine, Cardiff, United Kingdom.
Am J Med Genet. 2001 Jul 8;105(5):439-45. doi: 10.1002/ajmg.1404.
There is strong evidence for a genetic contribution to age at onset of schizophrenia, which probably involves both susceptibility loci for schizophrenia and modifying loci acting independent of disease risk. We sought evidence of linkage to loci that influence age at onset of schizophrenia in a sample of 94 affected sibling pairs with DSM-IV schizophrenia or schizoaffective disorder, and age at first psychiatric contact of 45 years or less. Individuals were genotyped for 229 microsatellite markers spaced at approximately 20 cM intervals throughout the genome. Loci contributing to age at onset were sought by a quantitative maximum-likelihood multipoint linkage analysis using MAPMAKER/SIBS. A nonparametric multipoint analysis was also performed. The genomewide significance of linkage results was assessed by simulation studies. There were six maximum-likelihood LOD score peaks of 1.5 or greater, the highest being on chromosome 17q (LOD = 2.54; genomewide P = 0.27). This fulfils Lander and Kruglyak's [1995: Nat Genet 11:241-247] criteria for suggestive linkage in that it would be expected to occur once or less (0.3 times) per genome scan. However, this finding should be treated with caution because the LOD score appeared to be almost solely accounted for by the pattern of ibd sharing at one marker (D17S787), with virtually no evidence of linkage over flanking markers. None of the linkage results achieved genomewide statistical significance, but the LOD score peak on chromosome 13q (LOD = 1.68) coincided with the region showing maximum evidence for linkage in the study by Blouin et al. [1998: Nat Genet 20:70-73] of categorical schizophrenia.
有强有力的证据表明，遗传因素对精神分裂症发病年龄有影响，这可能涉及精神分裂症的易感基因座以及独立于疾病风险起作用的修饰基因座。我们在一个由94对患病同胞组成的样本中寻找与影响精神分裂症发病年龄的基因座的连锁证据，这些同胞患有DSM-IV精神分裂症或分裂情感性障碍，且首次精神科接触年龄在45岁及以下。对个体进行了全基因组范围内约20 cM间隔分布的229个微卫星标记的基因分型。使用MAPMAKER/SIBS通过定量最大似然多点连锁分析寻找影响发病年龄的基因座。还进行了非参数多点分析。通过模拟研究评估连锁结果的全基因组显著性。有六个最大似然LOD得分峰值为1.5或更高，最高的在17号染色体q臂（LOD = 2.54；全基因组P = 0.27）。这符合兰德和克鲁格利亚克[1995年：《自然遗传学》11:241 - 247]提出的提示性连锁标准，即预计在每次全基因组扫描中出现一次或更少（0.3次）。然而，这一发现应谨慎对待，因为LOD得分似乎几乎完全由一个标记（D17S787）处的同源等位基因共享模式所解释，几乎没有侧翼标记连锁的证据。没有一个连锁结果达到全基因组统计学显著性，但13号染色体q臂上的LOD得分峰值（LOD = 1.68）与布卢万等人[1998年：《自然遗传学》20:70 - 73]关于分类精神分裂症的研究中显示出最大连锁证据的区域重合。
