Brain imaging correlates of molecular genetic risk types for schizophrenia and bipolar disorder

精神分裂症是一种常见的严重疾病，发病于成年早期。其病因、症状群和病程是异质的，已知受遗传控制。一项对12个双胞胎研究的荟萃分析估计，精神分裂症的遗传率为81%。除了遗传风险外，也有证据表明，重要的基因与环境的相互作用有助于总体责任。连锁研究已经确定了一系列可能含有易感基因的染色体区域，并在这些区域中获得了一些非常有希望的关联发现（例如神经调节蛋白1 [NRG1]，精神分裂症基因1中断[DISC1]，儿茶酚- o -甲基转移酶[COMT]， d -氨基酸氧化酶激活因子[DAOA也称为G72]，肌营养不良蛋白结合蛋白1 [DTNBP1]和g蛋白信号传导调节因子4 [RGS4]）。在这些候选药物中，有几个也与双相情感障碍有关，如NRG1、DISC1和G72。研究人员先前的工作发现，这种疾病相关的变异对健康个体的一般认知、人格特征、神经激活水平和大脑结构有影响，在许多情况下，这与将精神分裂症患者与健康对照组进行比较时发现的模式非常相似。目前的建议旨在将这些结果扩展到患者身上。由于一些易感基因似乎对精神分裂症和双相情感障碍都有影响，因此在一定程度上质疑了已建立的严格诊断界限，因此打算在这些调查中包括这两个诊断组，以探索两种疾病之间基因型-表型关联的共性和特异性。要研究的表型包括神经心理学变量、人格特征、几种认知和社会认知范式中的神经激活、全脑和特定区域形态测定以及结构和功能连接。待研究的候选基因将包括上述变体NRG1、DISC1、G72、DTNBP1和RGS4，以及从全基因组关联研究中出现的新候选基因，如CACNA1C、ZNF804A、Neurogranin和TCF4。该建议的目的是为了更深入地了解发病途径以及这些易感基因的特异性，以及用于检测其对健康受试者和患者影响的方法的敏感性。

Schizophrenia is a common and severe disorder with an onset in early adulthood. Its aetiology, symptom clusters, and course are heterogeneous and are known to be under genetic control. A meta-analysis of 12 twin studies estimated heritability in liability to schizophrenia at 81%. In addition to genetic risk, there is also evidence for important gene by environment interactions contributing to overall liability. Linkage studies have identified a series of chromosomal regions that are likely to contain susceptibility genes, and highly promising association findings have been obtained for several genes in these regions (e.g. neuregulin 1 [NRG1], disrupted in schizophrenia gene 1 [DISC1], Catechol-O-methyl transferase [COMT], D-amino acid oxidase activator [DAOA also known as G72], dystrobrevin-binding protein 1 [DTNBP1] and regulator of G-protein signaling 4 [RGS4]). Among those candidates, several have also been implicated in bipolar disorder, such as NRG1, DISC1 and G72. Previous work of the investigators has found that the disorder related variants have an influence on general cognition, personality profiles, neural activation levels and brain structure in healthy individuals which is, in many cases, highly similar to the patterns found when comparing patients with schizophrenia to healthy controls. The current proposal aims at extending these results in patients. As several susceptibility genes seem to have an influence on schizophrenia as well as bipolar disorder - thus in part questioning the established strict diagnostic boundaries- it is intended to include these two diagnostic groups in these investigations in order to explore the commonalities as well as specificities of the genotype-phenotype associations across the two disorders. The phenotypes to be investigated include neuropsychological variables, personality profiles, neural activations during several cognitive and social-cognitive paradigms, whole brain and area specific morphometry as well as structural and functional connectivity. Candidate genes to be investigated will include – among others – the above mentioned variants NRG1, DISC1, G72, DTNBP1, and RGS4, but also new candidates emerging from genome-wide associations studies such as e.g. CACNA1C, ZNF804A, Neurogranin and TCF4. The aim of the proposal is to gain a deeper understanding of the pathogenetic pathways as well as the specificity of these susceptibility genes and the sensitivity of the methods employed to detect their influence in healthy subjects and patients.