Translating OCD GWAS findings into mice: identifying epistatic modifiers of BTBD3

将 OCD GWAS 研究结果转化为小鼠：识别 BTBD3 的上位修饰因子

• 批准号: 8773096
• 负责人: STEPHANIE C DULAWA
• 金额: $ 23.7万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8773096
• 关键词: Accounting; Affect; Alleles; Animal Model; Anxiety Disorders; Autistic Disorder; Axon; Barbering; Behavior; Behavioral; Bipolar Disorder; Complex; Cystic Fibrosis; Data; Data Set; Databases; Dendrites; Development; Disease; Exhibits; Exploratory Behavior; Family; Functional disorder; Genes; Genetic; Genetic Engineering; Genetic Epistasis; Genetic screening method; Genome; Genotype; Gilles de la Tourette syndrome; Grooming; Hereditary Disease; Heritability; Heterozygote; Human; Human Genetics; Human Genome; Image; Inbred Strain; Inbreeding; Inherited; Knock-out; Knockout Mice; Maps; Modeling; Mus; Mutation; Neocortex; Obsession; Obsessive compulsive behavior; Obsessive-Compulsive Disorder; Phenotype; Population; Predisposition; Probability; Recombinant Inbred Strain; Reporting; Research Design; Resolution; Risk Factors; Sampling; Schizophrenia; Science; Single Nucleotide Polymorphism; Source; Spatial Behavior; Susceptibility Gene; Techniques; Testing; Therapeutic Intervention; Thinking; Translating; Variant; Work; Writing; base; behavior influence; cohort; design; disability; experience; genome wide association study; genome-wide; human disease; improved; innovation; interest; member; mutant; neural circuit; neuropsychiatry; novel; novel strategies; prepulse inhibition; programs; public health relevance; risk variant; screening; trait; transcription factor

DESCRIPTION (provided by applicant): Obsessive-compulsive disorder (OCD) is a severe anxiety disorder characterized by unwanted and intrusive thoughts, images, or impulses and/or repetitive behavior. OCD affects 1-3% of the world's population and is a leading cause of illness-related disability. Recently, the first genome-wide association study (GWAS) of OCD found a SNP, rs6131295, that achieved genome-wide significance in the trio portion of the sample. The gene closest to rs6131295 is BTBD3, and variation at this SNP regulates expression levels of BTBD3. BTBD3 is a member of a large family of transcription factors including BTBD9, a gene associated with Tourette's Syndrome (TS), a disorder frequently comorbid with OCD. We examined BTBD3 knockout (KO) mice for phenotypes relevant to OCD. Rather than considering BTBD3 KO mice a model for OCD as a categorical disorder, we focused on several behavioral domains including exploratory behavior, repetitive/compulsive behavior, and sensorimotor gating, that are altered in OCD and other related disorders including TS and autism. We found that BTBD3 KO mice exhibit increases in repetitive/compulsive behaviors, and reductions in exploratory behavior and sensorimotor gating. Our findings that BTBD3 KO mice have deficits across these domains increase the probability that BTBD3 was a "true hit" in the OCD GWAS. Far fewer risk genes have been identified for OCD than for other neuropsychiatric disorders such as schizophrenia and bipolar disorder, so increasing the number of genes that predispose to OCD would be highly significant. This proposal will use a novel F1 screening strategy in mice to identify epistatic modifiers of BTBD3. We will cross inbred C57BL/6J mice that are heterozygous for a KO allele of BTBD3 with 33 different inbred strains to produce large a F1 cohort. Half of the F1s will be wild type (WT), and half will be heterozygotes (HT) at the BTBD3 locus. F1 mice will be efficiently phenotyped for the behavioral traits we found to be altered in BTBD3 HT mice, including exploratory behavior, repetitive/compulsive behavior, and sensorimotor gating. These data will reveal which F1 genetic backgrounds modify the behavioral effects of carrying the BTBD3 KO allele. We will then perform a murine GWAS to identify genetic modifiers of BTBD3. Minimal genotyping will be required, since all of the genome besides the BTBD3 locus will be predicted from existing SNP databases. The genetic modifiers of murine BTBD3 that we identify can then be tested in the human GWAS datasets that were used to identify rs6131295 as a risk allele for OCD, and large GWAS datasets for TS and autism. This novel approach should greatly improve the power to detect epistatic modifiers in human genetic datasets by prioritizing specific comparisons and drastically reducing the number of statistical tests performed. Our approach could provide a novel strategy for identifying epistatic modifiers. Identifying genes that interact with BTBD3 will further our understanding of OCD susceptibility and pathophysiology, and other disorders involving similar behavioral domains including TS and autism.

描述(申请人提供)：强迫症(OCD)是一种严重的焦虑症，其特征是不想要的和侵入性的想法、图像、冲动和/或重复的行为。强迫症影响着世界1-3%的人口，是与疾病相关的残疾的主要原因。最近，强迫症的第一个全基因组关联研究(GWAS)发现了一个SNP，rs6131295，在样本的三个部分实现了全基因组意义。与rs6131295最接近的基因是BTBD3，该SNP的变异调节了BTBD3的表达水平。BTBD3是包括BTBD9在内的一个转录因子大家族的成员，BTBD9是一个与多发性抽动症(TS)相关的基因，TS是一种经常与强迫症共存的疾病。我们研究了BTBD3基因敲除(KO)小鼠与强迫症相关的表型。我们没有将BTBD3 KO小鼠作为强迫症的模型，而是将其视为一种绝对的障碍，我们专注于几个行为领域，包括探索行为、重复/强迫行为和感觉运动门控，这些行为领域在强迫症和其他相关障碍(包括TS和自闭症)中都会发生变化。我们发现BTBD3KO小鼠表现出重复/强迫行为的增加，探索行为和感觉运动门控的减少。我们的研究发现，BTBD3 KO小鼠在这些区域都存在缺陷，这增加了BTBD3在强迫症GWAS中获得“真正成功”的可能性。与精神分裂症和双相情感障碍等其他神经精神疾病相比，已确定的强迫症风险基因要少得多，因此增加易患强迫症的基因数量将具有非常重要的意义。这项提议将在小鼠中使用一种新的F1筛选策略来确定BTBD3的上位修饰因子。我们将BTBD3的KO等位基因杂合子的近交系C57BL/6J小鼠与33个不同的近交系品系杂交，产生一个大的F1队列。一半的F1将是野生型(WT)，另一半将是BTBD3基因座的杂合子(HT)。对于我们发现在BTBD3HT小鼠中发生改变的行为特征，F1小鼠将有效地进行表型鉴定，包括探索行为、重复/强迫行为和感觉运动门控。这些数据将揭示哪些F1遗传背景改变了携带BTBD3 KO等位基因的行为影响。然后，我们将进行小鼠GWA以确定BTBD3的遗传修饰物。将需要最小的基因分型，因为除了BTBD3基因座之外的所有基因组都将从现有的SNP数据库中预测出来。然后，我们确定的小鼠BTBD3的遗传修饰物可以在用于确定rs6131295是强迫症的风险等位基因的人类Gwas数据集中进行测试，以及在TS和自闭症的大型Gwas数据集中进行测试。这种新的方法应该可以通过区分特定比较的优先顺序和大幅减少执行的统计测试的数量来极大地提高在人类基因数据集中检测上位性修饰的能力。我们的方法可以为识别上位性修饰语提供一种新的策略。识别与BTBD3相互作用的基因将 进一步了解强迫症的易感性和病理生理学，以及其他涉及类似行为领域的障碍，包括TS和自闭症。