Genetics of Hippocampal Deficits in Bipolar Disorder

双相情感障碍海马缺陷的遗传学

• 批准号: 7065663
• 负责人: HILARY Patricia BLUMBERG
• 金额: $ 33.45万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-12 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7065663
• 关键词: adolescence (12-20); bioimaging /biomedical imaging; bipolar depression; brain derived neurotrophic factor; brain morphology; clinical research; gene expression; genetic polymorphism; genetic screening; genotype; hippocampus; human genetic material tag; human middle age (35-64); human subject; magnetic resonance imaging; neurogenetics; neuroimaging; neuropathology; serotonin transporter; suicide; young adult human (21-34)

DESCRIPTION (provided by applicant): The goal of the proposed work is to investigate the effect of polymorphic variation in the genes encoding brain-derived neurotrophic growth factor (BDNF) and a serotonin transporter promoter protein (locus, SLC6A4; variant, 5-HTTLPR) on hippocampal volume in bipolar disorder (BD). BD affects approximately 1% of individuals and is associated with significant suffering and a high suicide rate. Treatments are often ineffective, as understanding of the neuropathophysiology of the disorder is limited by a paucity of study. The identification of a neural endophenotype associated with a specific biochemical mechanism (and a specific genotype) could provide key information to aid development of earlier detection and targeted treatment strategies. Effects of genetic variation at the BDNF and SLC6A4 5-HTTLPR loci on the development of abnormalities in hippocampal volume in BD are implicated by associations to BD of polymorphisms in genes encoding BDNF and the SLC6A4, and by major effects of variations in BDNF and serotonin on hippocampal development. Reciprocal regulatory effects between BDNF and serotonin in their modulation of hippocampal development suggest interaction between genetic variation at the two loci on the development of hippocampal abnormalities in BD. Our pilot data provide evidence to support greater reductions in hippocampal volumes in BD in association with the BDNF Met allele, as compared to reductions that were also detected in association with this genotype in healthy individuals. We also detected decreased hippocampal volume in a BD subgroup who carry the low activity 5-HTTLPR "short" allele as compared to individuals with the "long"/"long" genotype. Moreover, our pilot data suggest interactions between the two genotypes in their influences on hippocampal volumes in BD. The proposed work, by a new investigator, employs structural magnetic resonance imaging to study influences of these genotypes on hippocampal volume in a BD group (N=100) and a healthy control group (N=100). To the best of our knowledge this is the first integrated neuroimaging and genetic study of modification of regional brain abnormalities in BD by genetic variations.

描述（由申请人提供）： 拟议的工作的目标是调查基因编码的脑源性神经营养生长因子（BDNF）和5-羟色胺转运蛋白启动子蛋白（位点，SLC 6A 4;变体，5-HTTLPR）的多态性变异对双相情感障碍（BD）海马体积的影响。BD影响大约1%的个体，并与显著的痛苦和高自杀率相关。治疗通常是无效的，因为对这种疾病的神经病理生理学的理解受到缺乏研究的限制。与特定生化机制（和特定基因型）相关的神经内表型的鉴定可以提供关键信息，以帮助开发早期检测和靶向治疗策略。BDNF和SLC 6A 4 5-HTTLPR基因座的遗传变异对BD海马体积异常发展的影响与BDNF和SLC 6A 4编码基因多态性与BD的关联以及BDNF和5-羟色胺变异对海马发育的主要影响有关。脑源性神经营养因子和5-羟色胺之间的相互调节作用，在他们的调制海马的发展表明在两个位点的遗传变异之间的相互作用，在BD海马异常的发展。我们的试验数据提供的证据支持更大的减少与BDNF Met等位基因相关的BD海马体积，相比，减少也检测到与健康个体中的这种基因型。我们还发现，与“长”/“长”基因型个体相比，携带低活性5-HTTLPR“短”等位基因的BD亚组海马体积减少。此外，我们的试点数据表明，两种基因型之间的相互作用，在BD海马体积的影响。 一位新的研究者提出的这项工作采用结构磁共振成像来研究这些基因型对BD组（N=100）和健康对照组（N=100）海马体积的影响。据我们所知，这是第一个综合神经影像学和遗传学研究的修改区域脑异常的遗传变异的BD。