Multi-Ethnic Genome-Wide Study of Bipolar Disorder

描述（由申请人提供）：双相情感障碍是一种常见的（占人群的1-2%）、使人衰弱和可能危及生命的精神疾病，其特征为抑郁和（轻度）躁狂的复发性、周期性发作。先前研究的证据强烈暗示双相情感障碍病因学的遗传基础。然而，确定易感性的遗传因素一直难以捉摸。最近的三项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，以检测可能构成这种疾病遗传基础的大量适度影响的关联。该项目是凯撒永久研究部和加州大学旧金山弗朗西斯科人类遗传学研究所的研究人员合作进行的。拟议研究的总体目标是通过对6，000例双相情感障碍病例和6，000例对照的种族多样性样本进行GWA研究，发现和表征可能与双相情感障碍风险相关的常见遗传变异，这些样本在北方加州地区（KPNC）的Kaiser Permanente医疗护理计划成员中确定。将从纵向电子病历（EMR）中识别病例和对照。为了增加表型同质性，采样框架将限于具有多次治疗发作的双相I型障碍个体。对照将与性别、当前年龄、自我认定的种族-民族、邮政编码和KPNC成员资格长度的病例频率匹配。收集唾液样本以获得DNA将得到凯撒永久基因、环境和健康研究计划的支持。遗传分析将在UCSF人类遗传学和基因组学核心设施研究所进行。本研究的具体目的是使用Affytron 6.0芯片平台在上述病例和对照组中进行双相I型障碍的GWA研究。我们将分析大约90万个单核苷酸多态性（SNP）和相似数量的拷贝数探针，以评估基因型和单倍型频率以及拷贝数变异的潜在病例对照差异。将对每个种族子样本进行人群分层检查，并评价各种族组结果的一致性。将通过考虑大量检测的变体来确定形式显著性。相关的表型，如精神病症状的存在或发病年龄，也将被评估与全基因组扫描的SNP的潜在关联。将利用类似的GWA研究数据进行合作研究，以验证我们自己和他人研究的重要发现。双相情感障碍是一种相对常见的精神疾病，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已经被强烈地牵连。在大的，充分表征的样本中进行全基因组关联研究，例如所提出的样本，可以提供有关增加双相情感障碍风险的特定遗传因素的信息，可能会增加对该疾病潜在原因的理解，并提供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.