重性精神疾病间存在共病、共易感基因、共表型的现象，提示疾病间可能存在重叠发病机制。本课题计划以同时具有重性抑郁障碍、精神分裂症、双向情感障碍三种疾病的一个家系为切入点，采用“家系发现”+“散发验证”+“功能学解释”的研究策略，系统阐述精神疾病的复杂遗传学模式。工作将通过深度测序和芯片检测的方法，在家系中初筛到可能与三种疾病均相关的“通用（表观）遗传因素”和仅与某种疾病相关的“特定（表观）遗传因素”若干，然后在三种疾病的大样本散发病例和健康人群进行多重过滤，对最终确认与三种疾病均相关的“通用因素”和导致疾病向三个方向分化的“分支点因素”，开展系统的人体内/体外功能学研究和模式动物研究，深入说明在重性精神疾病发生、发展和分化的过程中，各疾病相关因素间的协同作用机制。本工作的研究成果不但能对未来精神疾病的客观分子分类提供理论依据，而且对于如何抽丝剥茧地化解复杂疾病遗传学研究的复杂性提供了新思路。

Different mental disorders could share same susceptibility genes and partial clinic phenotypes, suggesting that there may have overlapped pathogenesis among them. Based on a consanguineous and multiplex pedigree, with 4 schizophrenia, 4 bipolar disorder, 9 major depressive disorders and 36 healthy individuals, we aim to elucidate this complex genetic patterns by a novel research strategy, including a combination of discovery in pedigree, verification in sporadic cases and functional explanation in cells and animals. We expect to identify the following two kinds of susceptibility genes through deep sequencing and microarray. One is specific for certain mental disorder, another is shared in two or more mental diseases. We will then validate these genes in large scale sporadic cases and healthy populations, and performed functional experiments in vitro and in vivo, to explain the possible synergistic mechanisms of universal variants or specific ones in the development and differentiation of mental diseases. This work will not only provide theoretical basis for molecular classification of mental diseases, but also offer new insights into unraveling the genetics of complex diseases.