A genome-wide scan for linkage to chromosomal regions in 382 sibling pairs with schizophrenia or schizoaffective disorder
A genome-wide scan for linkage to chromosomal regions in 382 sibling pairs with schizophrenia or schizoaffective disorder
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DOI：
10.1176/appi.ajp.159.5.803
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发表时间：
2002-05-01
影响因子：
17.7
通讯作者：
Sherrington, R
中科院分区：
文献类型：
--
作者：
DeLisi, LE;Shaw, SH;Sherrington, R
目的：一些精神分裂症易感基因的全基因组扫描和关联研究已经取得了显著的积极成果，但对它们的位置的研究之间存在分歧，并且尚未在任何基因中发现突变。由于精神分裂症是一种复杂的疾病，因此有必要进行一项具有足够功效的研究，以检测具有小或中度基因效应的位点。在对诊断为精神分裂症或情感障碍的382对兄弟姐妹进行全基因组扫描时，在所有个体中对整个基因组中间隔约10厘摩的396个高度多态性标记进行了基因分型。进行多点非参数连锁分析，以评估基因组区域显示等位基因共享增加，如通过lod评分测量的。发现两个具有多点最大lod值的连锁区域，最大lod值出现在染色体10 p15-p13（在标记D10 S189处的峰值lod得分为3.60）和2号染色体的着丝粒区域（在标记D2 S139处的峰值lod得分为2.99）。此外，在染色体22 q12上观察到标记D22 S283的最大lod得分为2.00，这表明存在印记效应的证据，由此存在过量的母系而非父系等位基因共享。在以往的研究中发现的几个位点，包括染色体1 q、4p、5 p-q、6p、8 p、13 q、15 p和18 p，均未获得连锁的证据。结论：这次大范围的全基因组扫描的结果强调了精神分裂症连锁报道的薄弱性和脆弱性。在大型研究中，似乎没有一致的可复制联系。因此，人们不得不质疑这种疾病的遗传贡献是否可以通过这些策略检测到，并且提出了它可能是表观遗传的可能性，即，与基因表达有关，而不是序列变异。然而，对2号、10号和22号染色体的阳性发现应进一步追踪。
Objective: Some genome-wide scans and association studies for schizophrenia susceptibility genes have yielded significant positive findings, but there is disagreement between studies on their locations, and no mutation has yet been found in any gene. Since schizophrenia is a complex disorder, a study with sufficient power to detect a locus with a small or moderate gene effect is necessary.Method. In a genome-wide scan of 382 sibling pairs with a diagnosis of schizophrenia or schizoaffective disorder, 396 highly polymorphic markers spaced approximately 10 centimorgans apart throughout the genome were genotyped in all individuals. Multipoint nonparametric linkage analysis was performed to evaluate regions of the genome demonstrating increased allele sharing, as measured by a lod score.Results: Two regions with multipoint maximum led scores suggesting linkage were found. The highest lod scores occurred on chromosome 10p15-p13 (peak lod score of 3.60 at marker D10S189) and the centromeric region of chromosome 2 (peak led score of 2.99 at marker D2S139). In addition, a maximum lod score of 2.00 was observed with marker D22S283 on chromosome 22q12, which showed evidence of an imprinting effect, whereby an excess sharing of maternal, but not paternal, alleles was present. No evidence of linkage was obtained at several locations identified in previous studies, including chromosomes 1q, 4p, 5p-q, 6p, 8p, 13q, 15p, and 18p.Conclusions: The findings of this large genome-wide scan emphasize the weakness and fragility of linkage reports on schizophrenia. No linkage appears to be consistently replicable across large studies. Thus, it has to be questioned whether the genetic contribution to this disorder is detectable by these strategies and the possibility raised that it may be epigenetic, i.e., related to gene expression rather than sequence variation. Nevertheless, the positive findings on chromosome 2, 10, and 22 should be pursued further.