Mapping Genes for comorbidity of SUDs and Depression

描述(由申请人提供)：本K01申请寻求支持额外的研究培训，使候选人能够致力于解开物质使用障碍和抑郁症(SODS+D)共病的遗传基础。具体地说，在人类SUD+D的分子遗传学和神经生物学专题上寻求进一步的培训，以及在寻找与SUD+D相关的内表型以及分析大量的基因分型数据方面的培训。还寻求精神病学和环境评估方法方面的培训，重点是有压力的童年经历。培训目标将通过两个研究项目来推进。项目1是利用NIDA资助的两个R01确定的样本和数据进行的二次分析，其主要目的是利用遗传连锁方法识别存在SUDS+D风险变异的遗传区域。由于连锁方法的固有局限性，识别的区域将是广泛的，并且可能包含许多基因。项目2将继续缩小遗传区域以定位候选基因，即通过连锁不平衡方法精细定位易患SODS+D的基因。它还将重点测试环境调节剂，如童年虐待，并将测试性行为对疾病易感性的影响。项目2将进一步研究染色体11q23上的一个基因簇，该基因簇包含四个SUDS候选风险基因：NCAM1、TTC12、ANKK1和DRD2。这位候选人计划在耶鲁大学和校外地点进行授课，以增强她在开展精神病学遗传学研究方面的专业知识。她将得到乔尔·格勒恩特、琼·考夫曼和赵宏宇博士的指导。他们都是备受推崇的科学家，非常有资格指导候选人的职业发展计划。最终目标是促进候选人转变为一名独立的精神遗传学家，致力于寻找在精神遗传学中重要的肥皂水、抑郁症和其他表型的遗传和环境风险因素。 与公共卫生相关：药物使用障碍和抑郁症的发生率很高，是精神障碍，对受影响的个人、其家庭和整个社会都有严重的后果。确定这种共病的遗传和环境原因可以对有效治疗和预防战略的设计产生重大影响，并履行NIDA的使命。

DESCRIPTION (provided by applicant): This K01 application seeks support for additional research training to enable the candidate to work towards unraveling the genetic basis for comorbidity of substance use disorders and depression (SUDs+D). Specifically, further training is sought in the topics of human molecular genetics and neurobiology of SUD+D, as well as training in the search for endophenotypes relevant to SUDs+D, and the analysis of large quantities of genotyping data. Training is also sought in psychiatric and environmental assessment methods, focusing on stressful childhood experiences. The training goals will be advanced through two research projects. Project 1 is a secondary analysis using samples and data ascertained through two NIDA-funded R01s, and its primary aim is to identify genetic regions harboring risk variants for SUDs+D using genetic linkage methods. Due to the inherent limitations of linkage methods, the identified region will be broad and will likely contain many genes. Project 2 will follow up in narrowing down the genetic regions so as to locate candidate genes, i.e., fine mapping the genes that are predisposing to SUDs+D through linkage disequilibrium methods. It will also focus on testing environmental modifiers such as childhood maltreatment, and will test the effect of sex on disease predisposition. Project 2 will further investigate a gene cluster on chromosome 11q23 which contains four candidate risk genes of SUDs: NCAM1, TTC12, ANKK1 and DRD2. The candidate plans to take didactic coursework at both Yale and off-campus sites to enhance her expertise in conducting psychiatric genetics research. She will be mentored by Drs. Joel Gelernter, Joan Kaufman and Hongyu Zhao. They are all highly regarded scientists and are exceedingly qualified to guide the candidate's career development plan. The ultimate goal is to facilitate the candidate's transition into an independent psychiatric geneticist devoted to finding the genetic and environmental risk factors for the comorbid SUDs and depression and other phenotypes important in psychiatric genetics. PUBLIC HEALTH RELEVANCE: Substance use disorders and depression, which co-occur at a high rate, are psychiatric disorders that have serious consequences for the affected individuals, their families, and all of society. Identifying genetic and environmental causes of this comorbidity can have a significant impact on the design of effective treatments and prevention strategies, and fulfills NIDA's mission.