Mapping genes that contribute to bipolar disorder

绘制导致躁郁症的基因图谱

• 批准号: 7969386
• 负责人: Francis J McMahon
• 金额: $ 136.85万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7969386
• 关键词: Adoption; Affect; Amygdaloid structure; Attention deficit hyperactivity disorder; Binding; Biological; Bipolar Disorder; Blood specimen; Brain; Candidate Disease Gene; Case-Control Studies; Cause of Death; Cell Adhesion; Cessation of life; Chromosome Mapping; Chromosomes; Chromosomes, Human, Pair 3; Clinical; Collaborations; Complex; DNA; DNA analysis; Diagnosis; Diagnostic; Disease; Etiology; Family; Functional Magnetic Resonance Imaging; Functional disorder; Gene Expression; Genes; Genetic; Genotype; Hereditary Disease; Individual; Interview; Intramural Research Program; Life; Maintenance; Major Depressive Disorder; Measures; Mediating; Meta-Analysis; Metabolism; Methods; Modeling; Mood Disorders; National Institute of Mental Health; Nature; Neurons; Occupational; Participant; Pathway interactions; Play; Positron-Emission Tomography; Prevention; Proteins; Public Health; Recruitment Activity; Research; Research Personnel; Risk; Risk Factors; Role; Sampling; Shapes; Siblings; Source; Suicide; Technology; Twin Multiple Birth; United States; Variant; Work; Zinc; age group; base; clinical Diagnosis; design; disability; disorder risk; follow-up; genetic linkage; genome wide association study; molecular marker; neuroimaging; response; serotonin transporter; severe mental illness; social

In collaboration with 10 academic centers across the United States, we have recruited a large sample of families in which at least 2 siblings suffer from bipolar disorder or related mood disorders. This is the largest sample ever to participate in a genetic study of bipolar disorder. All research participants have undergone a diagnostic interview and provided a blood sample for DNA analysis. Genetic linkage studies have been performed using molecular markers evenly spaced across all chromosomes. These studies suggested several chromosomal regions may contain genes that contribute to bipolar disorder in these families. Ongoing work is aimed at identifying the actual genes involved. Using the latest genotyping chip technology and DNA pooling, we conducted the first genome-wide association study of bipolar disorder. The results implicated several genes, each of small effect, suggesting that bipolar disorder is a polygenic disease. Meta-analysis of independent case-control studies of bipolar disorder supported association with several distinct genes that play a role in zinc metabolism (SLC39A3), cell adhesion (JAM3), and maintenance of normal neuronal functioning (ANK3). During the past year, we have begun functional studies of the implicated genes and markers. We have found that the JAM3 variant affects expression of this gene in the brain, suggesting that the amount of JAM3 protein in brain may mediate risk for bipolar disorder. We have also found evidence that 2 independent regions of the ANK3 gene are risk factors for bipolar disorder. Other meta-analyses have been designed to detect genes that play a role not only in bipolar disorder, but also in related conditions such as major depression and attention-deficit hyperactivity disorder. Using this approach, we recently found a cluster of closely-related markers on chromosome 3 that play a role in both bipolar disorder and major depression. The markers lie in a region with many genes, so our first task in following up this finding is to identify which of the genes is actually involved. In collaboration with other investigators at the NIMH Intramural Program, we have also investigated neuroimaging measures that have been associated with bipolar disorder and may reveal biological aspects of the disease. We have carried out candidate gene and genome-wide association studies of serotonin-transporter binding potential, as measured by positron emission tomography (PET), and amygdala activation, measured by functional magnetic resonance imaging (fMRI). These studies have implicated additional genes that were not detected in our studies based solely on the clinical diagnosis, suggesting other biological pathways that may be involved in mood disorders. Ongoing work is aimed at correlating our findings with those of other genome-wide association studies, studying the genes that seem to play the biggest role in disease risk, and identifying genes that help shape the clinical picture and response to treatment. We have also begun to explore multi-locus models that may better capture the multi-genic nature of this complex genetic disorder.

通过与美国10个学术中心的合作，我们招募了大量的家庭样本，其中至少有两个兄弟姐妹患有双相情感障碍或相关的情绪障碍。这是迄今为止参与双相情感障碍基因研究的最大样本。所有研究参与者都接受了诊断性访谈，并提供了血液样本进行DNA分析。遗传连锁研究使用均匀分布在所有染色体上的分子标记进行。这些研究表明，在这些家庭中，一些染色体区域可能包含导致双相情感障碍的基因。正在进行的工作旨在确定实际涉及的基因。