申请人17年来一直从事重性精神疾病发病机制研究：通过提出基于疾病相关通路的多基因联合作用分析策略，发现5种精神分裂症易感因素组合；并对这些组合采用多层面基因间作用模式研究，发现在精神疾病中存在基因间上位作用、顺式调节作用，并发现同一基因内部易感位点作用模式的不同可与不同精神疾病的易感性相关；发现6种基因与环境的联合作用与抑郁症相关；通过家系研究发现新的精神分裂症易感基因；发现2种外周血浆miRNA有作为精神分裂症标志物的潜力。建立了具有齐备临床资料的2万份精神疾病样本资料库。作为负责人先后承担国家级课题9项，发表通讯/第一作者SCI论文45篇（IF>10的7篇），多次获科技奖励和入选人才计划。申请人于2015年通过遗传学方法鉴定出2个新的抑郁症易感基因，发表在《自然》杂志，本申请将针对其中一个易感基因LHPP开展遗传、分子细胞和动物水平的全面研究，为抑郁症的发病机制和个体化治疗提供依据。

Dr. Xu is the principal investigator of studies aiming to localize genes and characterize pathological mechanisms for mental disorders including depression and schizophrenia. Her goal is to gain new insights into the mechanism of illness that should help develop new treatments. In the past 17 years, she has identified five genetic combination factors that are genetically predisposed to schizophrenia based on a polygenic conjoint analysis strategy. After that, she focused on the multi-layered gene-gene interactions and found evidence for epistasis between genes in schizophrenia and cis-phase interaction of genes in major depression that confer risks. She also demonstrated that different association of SNPs within the same gene could result in completely different disease phenotypes. Gene–environment interactions play important roles in the development of mental disorders. Dr. Xu has identified 6 genes meditating this interaction models. In a pedigree-based genetic study, Dr. Xu has identified a novel schizophrenia susceptibility gene with the help of deep sequencing. She reported that two plasma miRNAs can be used as biomarkers for schizophrenia and has the potential for clinical application. To date, Dr. Xu has established a mental disorder DNA bank of 20,000 samples with detailed clinical information. As the leader of national research projects, she has published 45 SCI articles (7 in high-ranking Journals with IF>10). She has been awarded several Ministerial and Provincial-Level Science and Technology Awards, and has been selected into China's National Talent Plan. A recent study by Dr. Xu has identified and replicated two genome-wide significant loci contributing to risk of MDD, which has been published on Nature. This proposal focuses on the molecular mechanisms of LHPP in the development of depression. We aim to use genetic and cell biological approaches and animal models to study the role of LHPP in depression. The goal of this study is to provide new insights of how LHPP confers risks for depression and to help develop new therapeutic strategy.