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。强迫症影响世界人口的1-3%，是疾病相关残疾的主要原因。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，在样本的三个部分中实现了全基因组意义。最接近rs6131295的基因是BTBD 3，该SNP的变异调节BTBD 3的表达水平。BTBD 3是包括BTBD 9的转录因子大家族的成员，BTBD 9是与抽动秽语综合征（TS）相关的基因，抽动秽语综合征是一种经常与强迫症共病的疾病。我们检查了BTBD 3敲除（KO）小鼠与OCD相关的表型。我们没有将BTBD 3 KO小鼠视为强迫症的模型，而是将重点放在几个行为领域，包括探索行为，重复/强迫行为和感觉运动门控，这些行为在强迫症和其他相关疾病（包括TS和自闭症）中发生改变。我们发现BTBD 3 KO小鼠表现出重复/强迫行为增加，探索行为和感觉运动门控减少。我们发现BTBD 3 KO小鼠在这些领域存在缺陷，这增加了BTBD 3在OCD GWAS中是“真正命中”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新型F1筛选策略来识别BTBD 3的上位性修饰剂。我们将BTBD 3的KO等位基因杂合的近交系C57 BL/6 J小鼠与33个不同的近交系杂交，以产生大的F1队列。在BTBD 3基因座，一半F1将是野生型（WT），一半将是杂合子（HT）。F1小鼠将被有效地分型为我们发现在BTBD 3 HT小鼠中改变的行为特征，包括探索行为、重复/强迫行为和感觉运动门控。这些数据将揭示哪些F1遗传背景改变携带BTBD 3 KO等位基因的行为效应。然后，我们将进行鼠GWAS以鉴定BTBD 3的遗传修饰剂。将需要最小的基因分型，因为除了BTBD 3基因座之外的所有基因组将从现有的SNP数据库中预测。我们鉴定的小鼠BTBD 3的遗传修饰因子可以在人类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。这种新的方法应该大大提高的权力，通过优先考虑特定的比较，并大大减少了统计测试的数量，以检测人类遗传数据集中的上位修饰符。我们的方法可以提供一个新的策略识别上位修饰语。识别与BTBD 3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疾病，包括TS和自闭症。

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.