Multi-Ethnic Genome-Wide Study of Bipolar Disorder

双相情感障碍的多种族全基因组研究

• 批准号: 8298603
• 负责人: CATHERINE Ann SCHAEFER
• 金额: $ 76.22万
• 依托单位: KAISER FOUNDATION RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8298603
• 关键词: Accounting; Address; Admixture; African American; Age; Age of Onset; American; Award; Behavioral; Biological; Bipolar Disorder; California; Candidate Disease Gene; Caring; Case-Control Studies; Code; Collaborations; Collection; Comorbidity; Computerized Medical Record; Copy Number Polymorphism; Core Facility; DNA; Data; Diagnosis; Disease; Enrollment; Environment; Ethnic Origin; Ethnic group; Etiology; Frequencies; Gender; Genes; Genetic; Genetic Predisposition to Disease; Genomics; Genotype; Goals; Haplotypes; Health; Heritability; Hospitalization; Human Genetics; Impairment; Individual; Institutes; Latino; Length; Life; Manic; Maps; Mediation; Medical; Mental Depression; Mental disorders; Minority Groups; Occupational; Outpatients; Pathway interactions; Pharmacotherapy; Phenotype; Population; Population Heterogeneity; Predisposition; Prevalence; Procedures; Psychotic Disorders; Race; Recording of previous events; Records Controls; Recurrence; Research; Research Personnel; Research Support; Resources; Risk; Risk Factors; Saliva; Sample Size; Sampling; San Francisco; Single Nucleotide Polymorphism; Social Functioning; Specimen; Stratification; Symptoms; Telephone Interviews; Testing; Universities; Variant; Visit; base; biobank; case control; follow-up; genetic analysis; genetic association; genetic epidemiology; genetic linkage analysis; genetic variant; genome wide association study; genome-wide; member; novel; programs; suicidal risk; validation studies

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.

描述（由申请人提供）：双相情感障碍是一种常见的（占人口的1-2%），使人衰弱并可能危及生命的精神疾病，其特征是反复发作，循环发作的抑郁症和（轻度）躁狂。先前研究的证据强烈暗示了双相情感障碍病因的遗传基础。然而，确定易感性的遗传因素一直难以捉摸。最近对双相情感障碍的三个全基因组关联（GWA）研究几乎没有产生强有力的关联。这些发现表明，该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，以检测可能构成该疾病遗传基础的大量关联，这些关联可能具有适度的影响。该项目是Kaiser Permanente研究部和加州大学旧金山人类遗传学研究所的研究人员的合作项目。该研究的总体目标是发现和描述可能与双相情感障碍风险相关的常见遗传变异，通过对6000例双相情感障碍和6000例对照的种族多样化样本进行GWA研究，确定在北加州地区（KPNC）凯撒永久医疗计划的成员中。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，采样框架将限于患有多次治疗发作的双相I型障碍的个体。对照将根据性别、当前年龄、自我认定的种族、邮政编码和KPNC会员资格的长短与病例进行频率匹配。收集唾液样本以获得DNA将由Kaiser Permanente基因、环境和健康研究计划提供支持。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研究所进行。本研究的具体目的是使用Affymetrix 6.0芯片平台对上述病例和对照组进行双相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化的潜在病例对照差异。将对每个民族子样本进行人口分层检查，并评估各民族结果的一致性。正式意义将通过考虑测试的大量变体来确定。相关表型，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。将采用类似的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障碍，通常涉及职业和社会功能的损害以及自杀风险的增加。双相情感障碍的病因实际上是未知的；然而，先前的研究强烈地暗示了这种疾病的遗传基础。在大的、特征明确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，可能导致对该疾病潜在原因的进一步了解，以及更可靠的诊断和新的治疗方法。