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

描述（由申请人提供）：强迫症（OCD）是一种严重的焦虑障碍，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。强迫症影响了世界1-3%的人口，是导致疾病相关残疾的主要原因。最近，强迫症的首个全基因组关联研究（GWAS）发现了一个SNP rs6131295，该SNP在样本的三人部分中具有全基因组意义。与rs6131295最接近的基因是BTBD3，该SNP的变异调节着BTBD3的表达水平。BTBD3是包括BTBD9在内的转录因子大家族的成员，BTBD9是一种与图雷特综合症（TS）相关的基因，这是一种经常与强迫症共病的疾病。我们检测了BTBD3基因敲除（KO）小鼠与强迫症相关的表型。我们没有将BTBD3 KO小鼠作为强迫症的一种分类障碍，而是关注了在强迫症和其他相关疾病（包括TS和自闭症）中发生改变的几个行为领域，包括探索行为、重复/强迫行为和感觉运动门控。我们发现BTBD3 KO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。我们发现，BTBD3 KO小鼠在这些区域都有缺陷，这增加了BTBD3在强迫症GWAS中“真正受到打击”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，已经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是非常重要的。本研究将在小鼠中使用一种新的F1筛选策略来鉴定BTBD3的上位性修饰因子。我们将与33个不同的自交系杂交具有BTBD3 KO等位基因的C57BL/6J小鼠，以产生一个大的F1队列。一半的F1s将是野生型（WT），一半将是杂合子（HT）在BTBD3位点。我们发现BTBD3 HT小鼠改变了F1小鼠的行为特征，包括探索行为、重复/强迫行为和感觉运动门控，这些特征将被有效地表型化。这些数据将揭示哪些F1遗传背景会改变携带BTBD3 KO等位基因的行为影响。然后，我们将进行小鼠GWAS来鉴定BTBD3的遗传修饰因子。由于除了BTBD3位点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。我们鉴定的小鼠BTBD3基因修饰因子随后可以在人类GWAS数据集中进行测试，这些数据集用于鉴定rs6131295作为强迫症的风险等位基因，以及用于TS和自闭症的大型GWAS数据集。这种新颖的方法应该大大提高能力，以检测上位调节剂在人类遗传数据集中，优先考虑特定的比较，并大大减少执行的统计测试的数量。我们的方法可以为识别上位性修饰语提供一种新的策略。确定与BTBD3相互作用的基因将会

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.