Genetics of Hippocampal Deficits in Bipolar Disorder

双相情感障碍海马缺陷的遗传学

• 批准号: 6869703
• 负责人: HILARY Patricia BLUMBERG
• 金额: $ 33.44万
• 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/6869703
• 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)： 本研究的目的是研究双相情感障碍(BD)患者脑源性神经营养生长因子(BDNF)和5-羟色胺转运体启动子蛋白(SLC6A4；5-HTTLPR)基因的多态变异对其海马体体积的影响。BD影响大约1%的个体，并与巨大的痛苦和高自杀率相关。治疗往往是无效的，因为对这种疾病的神经病理生理学的了解受到研究匮乏的限制。识别与特定生化机制(和特定基因)相关的神经内表型可以提供关键信息，以帮助开发早期检测和有针对性的治疗策略。BDNF和SLC6A4 5-HTTLPR基因座的遗传变异对BD患者海马体积异常的影响可能与BD相关，BDNF和SLC6A4编码基因的多态与BD的发生有关，BDNF和5-羟色胺的变异对BD的影响也是重要的。脑源性神经营养因子和5-羟色胺在调节海马区发育中的相互调节作用提示，这两个基因座的遗传变异在BD海马区异常的发生发展中存在交互作用。我们的先导数据提供了证据，支持与BDNF Met等位基因相关的BD患者的海马体体积更大程度地减少，而在健康个体中也检测到与该基因相关的减少。我们还发现，与携带“长”/“长”基因的个体相比，携带低活性5-HTTLPR“短”等位基因的BD亚组的海马体体积减少。此外，我们的初步数据表明，在BD患者中，这两种基因型之间的交互作用对其海马体体积的影响。 这项由一位新研究人员提出的工作，利用结构磁共振成像技术，在BD组(N=100)和健康对照组(N=100)中研究了这些基因对海马体体积的影响。据我们所知，这是第一次通过基因变异改变BD患者局部脑异常的神经影像和遗传学综合研究。