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，在成年早期发病。其病因、症状群和病程是异质的，并且已知受遗传控制。一项对12项双胞胎研究的荟萃分析估计，精神分裂症的遗传易感性为81%。除了遗传风险外，还有证据表明，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包含易感基因的染色体区域，并且在这些区域中的几个基因中获得了非常有希望的关联发现（例如神经调节蛋白1 [NRG 1]，在精神分裂症基因1 [DISC 1]中被破坏，儿茶酚-O-甲基转移酶[COMT]，D-氨基酸氧化酶激活剂[DAOA，也称为G72]，肌萎缩蛋白结合蛋白1 [DTNBP 1]和G蛋白信号传导调节因子4 [RGS 4]）。在这些候选人中，有几个也与双相情感障碍有关，如NRG 1，DISC 1和G72。研究人员先前的工作发现，与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，这与精神分裂症患者与健康对照组相比时发现的模式高度相似。目前的建议旨在将这些结果扩展到患者。由于几个易感基因似乎对精神分裂症和双相情感障碍有影响，因此部分质疑了已建立的严格诊断界限，因此打算在这些研究中包括这两个诊断组，以探索这两种疾病的基因型-表型关联的共性和特异性。待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期间的神经激活、全脑和区域特异性形态测量以及结构和功能连接。待研究的候选基因将包括上述变体NRG 1、DISC 1、G72、DTNBP 1和RGS 4，以及从全基因组关联研究中出现的新候选基因，例如CACNA 1C、ZNF 804 A、神经颗粒蛋白和TCF 4。该提案的目的是更深入地了解致病途径以及这些易感基因的特异性和用于检测其在健康受试者和患者中的影响的方法的灵敏度。

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.