Association of DISC1/TRAX haplotypes with schizophrenia, reduced prefrontal gray matter, and impaired short- and long-term memory
Association of DISC1/TRAX haplotypes with schizophrenia, reduced prefrontal gray matter, and impaired short- and long-term memory
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DOI：
10.1001/archpsyc.62.11.1205
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发表时间：
2005-11-01
影响因子：
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通讯作者：
Peltonen, L
中科院分区：
文献类型：
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作者：
Cannon, TD;Hennah, W;Peltonen, L
背景：1号染色体42区是显示出与精神分裂症存在连锁重复证据的几个基因组区域之一，但这种关系背后的具体易感机制仍有待确定。
目的：检查来自1号染色体42区一段跨越精神分裂症断裂基因1（DISC1）和转位相关因子X（TRAX）基因的单核苷酸多态性标记的一系列单倍型模块，以确定其与精神分裂症以及几种被认为与疾病发病机制有关的内表型特征的关联。
设计：基于人群的双胞胎队列研究。
地点：芬兰。
参与者：236名受试者，包括7对精神分裂症同病一致的双胞胎（6对同卵[MZ]和1对异卵[DZ]），52对精神分裂症不一致的双胞胎（20对MZ和32对DZ），以及59对人口统计学上平衡的正常双胞胎（28对MZ和31对DZ），这些受试者来自1940年至1957年在芬兰出生的所有同性双胞胎组成的队列。
主要观察指标：精神疾病诊断、短期和长期记忆的神经认知测试表现，以及从高分辨率磁共振图像获取的灰质体积测量值。
结果：在DISC1易位断点附近包含3个单核苷酸多态性标记的一种常见单倍型（优势比为2.6[P = 0.02]）以及包含来自DISC1和TRAX基因的4个标记的一种罕见单倍型（优势比为13.0[P = 0.001]）在精神分裂症患者中显著过度表达。这些单倍型还与先前观察到的与精神分裂症及精神分裂症遗传易感性共变的几种定量内表型特征相关，包括短期和长期记忆功能受损以及前额叶皮质灰质密度降低，这是通过基于人群的脑图谱方法所证明的，并且有与海马体积减少相关的趋势。
结论：1号染色体42区的DISC1和TRAX基因的特定等位基因似乎通过对前额叶皮质、内侧颞叶和其他脑区的结构和功能的破坏作用而增加精神分裂症的遗传风险。这些作用与其产生的在神经突生长、神经元迁移、突触发生和谷氨酸能神经传递中起作用的蛋白质是一致的。
Context: Chromosome 1q42 is among several genomic regions showing replicated evidence of linkage with schizophrenia, but the specific susceptibility mechanisms underlying this relationship remain to be identified.Objective: To examine a series of haplotype blocks of single-nucleotide polymorphic markers from a segment of 1q42 spanning the disrupted-in-schizophrenia 1 (DISC1) and translin-associated factor X (TRAX) genes for association with schizophrenia and several endophenotypic traits thought to be involved in disease pathogenesis.Design: Population-based twin cohort study.Setting: Finland.Participants: Two hundred thirty-six subjects, consisting of 7 twin pairs concordant for schizophrenia (6 monozygotic [MZ] and I dizygotic [DZ]), 52 pairs discordant for schizophrenia (20 MZ and 32 DZ), and 59 demographically balanced normal pairs (28 MZ and 31 DZ), were drawn from a twin cohort consisting of all of the same-sex twins born in Finland from 1940 through 1957.Main Outcome Measures: Psychiatric diagnosis, performance on neurocognitive tests of short- and long-term memory, and gray matter volume measurements taken from high-resolution magnetic resonance images.Results: A common haplotype incorporating 3 single-nucleotide polymorphic markers near the translocation break point of DISC1 (odds ratio, 2.6 [P=.02]) and a rare haplotype incorporating 4 markers from the DISC1 and TRAX genes (odds ratio, 13.0 [P=.001]) were significantly overrepresented among individuals with schizophrenia. These haplotypes were also associated with several quantitative endophenotypic traits previously observed to covary with schizophrenia and genetic liability to schizophrenia, including impairments in short- and long-term memory functioning and reduced gray matter density in the prefrontal cortex, as demonstrated using a population-based brain atlas method, with a trend toward association with reduced hippocampal volume.Conclusions: Specific alleles of the DISC1 and TRAX genes on 1q42 appear to contribute to genetic risk for schizophrenia through disruptive effects on the structure and function of the prefrontal cortex, medial temporal lobe, and other brain regions. These effects are consistent with their production of proteins that play roles in neuritic outgrowth, neuronal migration, synaptogenesis, and glutamatergic neurotransmission.