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: 8898917
• 负责人: STEPHANIE C DULAWA
• 金额: $ 19.75万
• 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 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8898917
• 关键词: Accounting; Affect; Alleles; Animal Model; Anxiety Disorders; Autistic Disorder; Axon; Barbering; Behavior; Behavioral; Bipolar Disorder; Complex; Compulsive Behavior; Cystic Fibrosis; Data; Data Set; Databases; Dendrites; Development; Disease; Exhibits; Exploratory Behavior; Family; Functional disorder; Genes; Genetic; Genetic Engineering; Genetic Epistasis; Genetic screening method; Genetic study; Genome; Genotype; Gilles de la Tourette syndrome; Grooming; Health; 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 Disorder; Pathological anxiety; 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; compulsion; 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; 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（由申请人提供）：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、图像或冲动和/或重复行为。强迫症影响着世界上 1-3% 的人口，是导致疾病相关残疾的主要原因。最近，第一个强迫症全基因组关联研究 (GWAS) 发现了一个 SNP，rs6131295，它在样本的三个部分中实现了全基因组显着性。与 rs6131295 最接近的基因是 BTBD3，该 SNP 的变异可调节 BTBD3 的表达水平。 BTBD3 是转录因子大家族的成员，其中包括 BTBD9，这是一种与抽动秽语综合征 (TS) 相关的基因，抽动秽语综合征 (TS) 是一种经常与强迫症共存的疾病。我们检查了 BTBD3 敲除 (KO) 小鼠与强迫症相关的表型。我们没有将 BTBD3 KO 小鼠视为强迫症的模型，而是将注意力集中在几个行为领域，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疾病（包括 TS 和自闭症）中发生了改变。我们发现 BTBD3 KO 小鼠表现出重复/强迫行为的增加，以及探索行为和感觉运动门控的减少。我们发现 BTBD3 KO 小鼠在这些领域存在缺陷，这增加了 BTBD3 在 OCD GWAS 中“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，已发现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非常重要。该提案将在小鼠中使用一种新颖的 F1 筛选策略来鉴定 BTBD3 的上位修饰剂。我们将把 BTBD3 KO 等位基因杂合的近交 C57BL/6J 小鼠与 33 个不同的近交品系杂交，产生大型 F1 群体。一半的 F1 是野生型 (WT)，一半是 BTBD3 基因座的杂合子 (HT)。 F1 小鼠将针对我们发现 BTBD3 HT 小鼠中发生改变的行为特征进行有效表型分析，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 遗传背景会改变携带 BTBD3 KO 等位基因的行为效应。然后我们将进行小鼠 GWAS 来鉴定 BTBD3 的遗传修饰剂。由于除了 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，因此需要最少的基因分型。我们确定的小鼠 BTBD3 的遗传修饰剂可以在人类 GWAS 数据集中进行测试，该数据集用于将 rs6131295 识别为 OCD 的风险等位基因，以及 TS 和自闭症的大型 GWAS 数据集。这种新颖的方法应该通过优先考虑特定比较并大幅减少执行的统计测试的数量，极大地提高检测人类遗传数据集中上位修饰符的能力。我们的方法可以提供一种识别上位修饰符的新策略。鉴定与 BTBD3 相互作用的基因将 进一步加深我们对强迫症易感性和病理生理学以及涉及类似行为领域的其他疾病（包括 TS 和自闭症）的理解。