Haplotype transmission analysis provides evidence of association for DISC1 to schizophrenia and suggests sex-dependent effects
Haplotype transmission analysis provides evidence of association for DISC1 to schizophrenia and suggests sex-dependent effects
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DOI：
10.1093/hmg/ddg341
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发表时间：
2003-12-01
影响因子：
3.5
通讯作者：
Ekelund, J
中科院分区：
文献类型：
--
作者：
Hennah, W;Varilo, T;Ekelund, J
我们以前曾报道在芬兰精神分裂症样本1q42的连锁峰。在这项研究中，我们从1q42的28个单核苷酸多态性（SNPs）的基因型，涵盖三个候选基因TRAX，DISC1和DISC2，使用458个芬兰家庭的研究样本确定为精神分裂症。两点和单倍型关联分析揭示了DISC1基因内的一个重要区域。观察到常见单倍型（HEP 3）向受影响个体的传播显着不足（P=0.0031）。HEP3代表从DISC1的内含子1到外显子2的两个SNP单倍型。该单倍型还显示了传输失真的性别差异，传输不足仅对受影响的女性显着（P=0.00024）。在TRAX和DISC基因中观察到其他三个感兴趣的区域。然而，仅对具有完整基因型信息的那些家族的分析特别突出了HEP3单倍型作为真实观察。一个常见的低传递SNP单倍型的发现可能意味着这个特定的等位基因提供了一些保护，从精神分裂症的发展。精神分裂症的组成特征的分析，来自精神疾病的操作标准检查表（OCCPI），显示HEP3与精神分裂症的一般表型特征相关，包括代表妄想，幻觉和阴性症状的特征。本研究为DISC1基因与精神分裂症病因学有关的假说提供了进一步的证据，并暗示该基因的作用存在假定的性别差异。我们的研究结果也将鼓励更详细的分析DISC1对精神分裂症的组成特征的影响。
We have previously reported a linkage peak on 1q42 in a Finnish schizophrenia sample. In this study we genotyped 28 single nucleotide polymorphisms (SNPs) from 1q42 covering the three candidate genes TRAX, DISC1 and DISC2, using a study sample of 458 Finnish families ascertained for schizophrenia. Two-point and haplotype association analysis revealed a significant region of interest within the DISC1 gene. A common haplotype (HEP3) was observed to be significantly under-transmitted to affected individuals (P=0.0031). HEP3 represents a two SNP haplotype spanning from intron 1 to exon 2 of DISC1. This haplotype also displayed sex differences in transmission distortion, the under-transmission being significant only to affected females (P=0.00024). Three other regions of interest were observed in the TRAX and DISC genes. However, analysis of only those families with complete genotype information specifically highlights the HEP3 haplotype as a true observation. The finding of a common under-transmitted SNP haplotype might imply that this particular allele offers some protection from the development of schizophrenia. Analysis of component-traits of schizophrenia, derived from the Operational Criteria Checklist of Psychotic Illness (OCCPI), displayed association of HEP3 to features of the general phenotype of schizophrenia, including traits representing delusions, hallucinations and negative symptoms. This study provides further evidence for the hypothesis that the DISC1 gene is involved in the aetiology of schizophrenia, and implies a putative sex difference for the effect of the gene. Our findings would also encourage more detailed analyses of the effect of DISC1 on the component-traits of schizophrenia.