The genetics of symptom-based phenotypes: toward a molecular classification of schizophrenia.
The genetics of symptom-based phenotypes: toward a molecular classification of schizophrenia.
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DOI：
10.1093/schbul/sbn076
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发表时间：
2008-11
影响因子：
6.6
通讯作者：
Malhotra AK
中科院分区：
文献类型：
--
作者：
DeRosse P;Lencz T;Burdick KE;Siris SG;Kane JM;Malhotra AK
精神分裂症的遗传连锁研究主要集中在疾病易感性的表型上。然而，有限数量的研究报告了与特定精神分裂症症状域（包括染色体6、8和20上的区域）的暗示性联系。我们使用一组密集的单核苷酸多态性（SNP）来检查这些染色体区域与阳性、阴性和紊乱症状簇的关联。我们确定了178例白人精神分裂症患者的终身严重程度的临床精神病学使用结构化诊断访谈。该队列用Affyestival 500K微阵列进行基因分型，我们从其中先验地选择了位于先前与特定精神分裂症症状簇相关的染色体区域内的4，833个基因内SNP。参数测试，校正多个测试，被用来比较这些SNP内的等位基因变异的影响，以终身严重程度的特定症状域，已牵连先前的连锁研究。我们能够扩展以前的报告染色体6q之间的联系和积极的和混乱的症状。阳性症状的终生严重程度与ORC3L的SNP显著相关（p=2.50 × 10−5），ORC3L是一种与突触可塑性有关的基因。紊乱症状的水平与BAI3中的两个SNP显著相关（p<6.00 × 10−5），BAI3在发育过程中在大脑中高度表达。这些数据指向特定的候选基因位于先前牵连的连锁峰的临床肿瘤学。需要鉴定这些区域内的功能变体，并表征这些风险基因型对治疗特定临床症状的影响。
Genetic linkage studies in schizophrenia have primarily focused on the phenotype of disease susceptibility. A limited number of studies, however, have reported suggestive linkage to specific schizophrenia symptom domains including regions on chromosomes 6, 8 and 20. We examined these chromosomal regions for association to positive, negative and disorganized symptom clusters, using a dense set of single nucleotide polymorphisms (SNPs). We ascertained 178 Caucasian patients with schizophrenia for lifetime severity of clinical symptomatology using a structured diagnostic interview. The cohort was genotyped with the Affymetrix 500K microarray, from which we selected, a priori, 4,833 intragenic SNPs located within chromosomal regions previously linked to specific schizophrenia symptom clusters. Parametric tests, corrected for multiple testing, were used to compare the effects of allelic variation within these SNPs to the lifetime severity of the specific symptom domain that had been implicated by prior linkage studies. We were able to extend previous reports of linkage between chromosome 6q and both positive and disorganized symptoms. Lifetime severity of positive symptoms was significantly (p=2.50 × 10−5) associated with a SNP in ORC3L, a gene implicated in synaptic plasticity. Level of disorganized symptoms was significantly (p<6.00 × 10−5) associated with two SNPs in BAI3, which is highly expressed in brain during development. These data point towards specific candidate genes located within previously implicated linkage peaks for clinical symptomatology. Identification of functional variants within these regions and a characterization of the effect of these risk genotypes on the treatment of specific clinical symptoms are needed.
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