The Molecular Genetics of Recurrent Major Depression in Chinese Women

描述(由申请人提供)：严重抑郁症(MD)在全球范围内造成大量的发病率和死亡率。MD的风险受到遗传风险因素的强烈影响。该项目试图通过结合丰富的表型指标和来自CELGE(中国，牛津大学和威斯康星大学遗传流行病学实验研究)项目的序列数据来阐明MD遗传风险的分子基础。Converge对6000名患有复发性MD的汉族女性和6000名伦理匹配的筛查对照组进行了详细的结构化采访。此外，为了比基因分型阵列更广泛和更深入地询问基因组，将从低通(LP)全基因组测序中获得基因类型。在Converge大小的样本中，该设计提供了对常见变异的全面测量，以及低于1-2%的次要等位基因频率的变异，这些变异从微阵列数据中无法得到很好的推算。LP全基因组测序和变种调用将在2012年利用外部资金完成。5,000例MD和5,000例对照的祖先匹配样本可用于复制。我们要求4年的支持，以进行i)临床表型分析，ii)分子统计分析，包括与已验证的环境风险因素的X基因环境相互作用分析，以及iii)复制分析。除了我们的大样本量，Converge项目有六个设计特点，最大限度地提高了我们能够澄清MD遗传风险因素的性质的可能性。我们招募了i)只招募有ii)汉族血统且有iii)复发疾病的女性。对于这些女性，我们仔细评估了四个关键的环境风险因素和五)非常丰富的表型特征，包括重要的合并症。最后，我们的控制组年龄相对较大，并经过了仔细的筛选，以确保患抑郁症的风险较低。识别影响MD风险的基因变异将为了解这种疾病的病理生理学机制和开发新的治疗和预防方法提供可能。

DESCRIPTION (provided by applicant): Major depression (MD) accounts for substantial worldwide morbidity and mortality. Risk for MD is strongly influenced by genetic risk factors. This project seeks to elucidate the molecular basis of the genetic risk for MD by combining the rich phenotypic measures and sequence data from the CONVERGE (China, Oxford and VCU Experimental Research on Genetic Epidemiology) project. CONVERGE obtained detailed structured interviews on 6,000 Han Chinese women with recurrent MD and 6,000 ethically matched screened controls. Furthermore, in order to interrogate the genome more broadly and more deeply than is possible with genotyping arrays, genotypes will be obtained from low pass (LP) whole genome sequencing. In a sample of the size of CONVERGE, the design provides comprehensive measurement of common variation together with variants at minor allele frequencies below 1-2%, which are poorly imputed from microarray data. LP whole genome sequencing and variant calling will be completed in 2012 using external funding. An ancestry matched sample of 5,000 cases of MD and 5,000 controls is available for replication. We request 4 years of support to conduct i) clinical-phenotypic, ii) molecular-statistical analyses, including gene X environmental interaction analyses with verified environmental risk factors, and iii) replication analyses. In addition to our large sample size, the CONVERGE project has six design features which maximize the probability that we will be able to clarify the nature of the genetic risk factors for MD. We have recruited i) only women who are of ii) Han Chinese ancestry and who have had iii) recurrent illness. For these women, we have carefully assessed iv) four key environmental risk factors and v) a very rich phenotypic profile including important co-morbidities. Finally, our controls are relatively elderly and have been carefully screened to ensure a low liability to depressive illness. The identification of genetic variants which impact o risk for MD would open up the possibility of understanding the pathophysiology of this disorder and developing new methods of treatment and prevention.