Multi-Ethnic Genome-Wide Study of Bipolar Disorder

描述(申请人提供)：双相情感障碍是一种常见的(1-2%的人口)，衰弱和潜在威胁生命的精神障碍，其特征是反复发作的周期性抑郁和(低)躁狂。来自先前研究的证据有力地暗示了双相情感障碍的病因学的遗传基础。然而，决定易感性的遗传因素的识别一直难以捉摸。最近三项关于双相情感障碍的全基因组关联(GWA)研究几乎没有产生强有力的关联。这些发现表明，这种疾病的遗传复杂性可能需要更大的样本量和更全面的遗传平台，以检测大量影响温和的关联，这些关联可能是这种疾病的遗传基础。这个项目是由凯撒永久研究部和加州大学旧金山人类遗传学研究所的研究人员合作完成的。这项拟议研究的总体目标是通过对北加州地区Kaiser Permanente Medical Care Plan(KPNC)成员中确定的6000例双相情感障碍患者和6000名对照的种族多样性样本进行GWA研究，发现并表征可能与双相情感障碍风险相关的常见基因变异。病例和对照将从纵向电子病历(EMR)中确定。为了增加表型的同质性，抽样范围将限于有多个治疗发作的双相I型障碍患者。对照措施将与性别、当前年龄、自我确认的种族族裔、邮政编码和在KPNC的成员年限的病例进行频率匹配。采集唾液样本以获取DNA将得到凯撒永久基因、环境和健康研究计划的支持。基因分析将在加州大学旧金山分校人类遗传学和基因组学核心设施进行。这项研究的具体目的是使用Affymetrix 6.0芯片平台在上述病例和对照中进行双相I型障碍的GWA研究。我们将分析大约90万个单核苷酸多态(SNPs)和类似数量的拷贝数探针，以评估在基因型和单倍型频率以及拷贝数变异方面潜在的病例对照差异。将对每个种族亚样本进行人口分层检查，并评估不同种族群体结果的一致性。正式意义将通过考虑大量测试的变种来确定。相关的表型，如精神病症状的存在或发病时的年龄，也将从全基因组扫描中评估与SNPs的潜在关联。将开展与GWA类似研究数据的合作研究，以验证我们自己和其他人的研究的重要发现。双相情感障碍是一种相对常见的精神障碍，通常涉及职业和社会功能受损以及自杀风险增加。双相情感障碍的原因几乎是未知的；然而，在以前的研究中，这种疾病的遗传基础被强烈地牵连起来。对大的、特征良好的样本进行全基因组关联研究，如所提出的一个，可以提供关于增加双相情感障碍风险的特定遗传因素的信息，潜在地导致对该疾病潜在原因的更多了解，以及更可靠的诊断和新的治疗方法。

DESCRIPTION (provided by applicant): Bipolar disorder is a common (1-2% of population), debilitating and potentially life-threatening psychiatric disorder that is characterized by recurrent, cyclic episodes of depression and (hypo)mania. Evidence from prior studies strongly implicates a genetic basis for the etiology of bipolar disorder. However, identification of the genetic factors that determine susceptibility has been elusive. Three recent genome-wide association (GWA) studies of bipolar disorder have produced few robust associations. These findings suggest that the genetic complexity of the disorder may require significantly larger sample sizes and a more comprehensive genetic platform, to detect the large number of associations with modest effects that may underlie the genetic basis of this disorder. This project is a collaboration of investigators at the Kaiser Permanente Division of Research and the University of California, San Francisco Institute for Human Genetics. The overall goal of the proposed study is to discover and characterize common genetic variants that may be associated with the risk of bipolar disorder, by conducting a GWA study of an ethnically diverse sample of 6,000 cases of bipolar disorder and 6,000 controls, ascertained among the members of the Kaiser Permanente Medical Care Plan, Northern California Region (KPNC). Cases and controls will be identified from longitudinal electronic medical records (EMR). To increase phenotypic homogeneity, the sampling frame will be limited to individuals with bipolar I disorder with multiple treatment episodes. Controls will be frequency-matched to cases on gender, current age, self- identified race-ethnicity, zip code, and length of membership in KPNC. Collection of saliva samples for obtaining DNA will be supported by the Kaiser Permanente Research Program on Genes, Environment and Health. Genetic analyses will be done at the UCSF Institute for Human Genetics and Genomics Core Facility. The specific aims for this study are to perform a GWA study of bipolar I disorder in the cases and controls described above using the Affymetrix 6.0 chip platform. We will analyze approximately nine hundred thousand single nucleotide polymorphisms (SNPs) and a similar number of copy number probes to assess potential case-control differences in genotype and haplotype frequencies, as well as copy number variation. Each ethnic subsample will be examined for population stratification, and consistency of results across ethnic groups will be evaluated. Formal significance will be determined by taking into account the large number of variants tested. Related phenotypes, such as the presence of psychotic symptoms or age at onset, will also be evaluated for potential associations with SNPs from the genome-wide scan. Collaborative studies with similar GWA study data will be undertaken to validate significant findings from our own and others' studies. Bipolar disorder is a relatively common psychiatric disorder that often involves impairment of occupational and social functioning and an increased risk of suicide. The causes of bipolar disorder are virtually unknown; however, a genetic basis for the disorder has been strongly implicated in previous studies. Genome-wide association studies in large, well-characterized samples such as the one proposed, can provide information about specific genetic factors that increase the risk of bipolar disorder, potentially leading to increased understanding of the underlying causes of the disorder, and to more reliable diagnoses and new treatments as well.