Whole genome analyses reveal significant convergence in obsessive-compulsive disorder between humans and dogs  

多组学研究揭示家犬和人强迫症之间显著的遗传趋同

作　　者：Xue Cao Wei-Peng Liu Lu-Guang Cheng Hui-Juan Li Hong Wu Yan-Hu Liu Chao Chen Xiao Xiao Ming Li Guo-Dong Wang Ya-Ping Zhang 曹雪;刘伟鹏;程鲁光;李慧娟;吴宏;柳延虎;陈超;肖潇;李明;王国栋;张亚平(State Key Laboratory of Genetic Resources and Evolution and Yunnan Laboratory of Molecular Biology of Domestic Animals,Kunming Institute of Zoology,Chinese Academy of Sciences,Kunming 650223,China;Department of Laboratory Animal Science,Kunming Medical University,Kunming 650500,China;Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province,Kunming Institute of Zoology,Chinese Academy of Sciences,Kunming 650223,China;Kunming College of Life Science,University of Chinese Academy of Sciences,Kunming 650223,China;Kunming Police Dog Base,Ministry of Public Security,Kunming 650204,China;Laboratory for Conservation and Utilization of Bio-resource&Key Laboratory for Microbial Resources of the Ministry of Education,Yunnan University,Kunming 650091,China;Center for Excellence in Brain Science and Intelligence Technology,Chinese Academy of Sciences,Shanghai 200031,China;KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases,Kunming Institute of Zoology,Chinese Academy of Sciences,Kunming 650223,China;Center for Excellence in Animal Evolution and Genetics,Chinese Academy of Sciences,Kunming 650223,China)

机构地区：[1]State Key Laboratory of Genetic Resources and Evolution and Yunnan Laboratory of Molecular Biology of Domestic Animals,Kunming Institute of Zoology,Chinese Academy of Sciences,Kunming 650223,China [2]Department of Laboratory Animal Science,Kunming Medical University,Kunming 650500,China [3]Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province,Kunming Institute of Zoology,Chinese Academy of Sciences,Kunming 650223,China [4]Kunming College of Life Science,University of Chinese Academy of Sciences,Kunming 650223,China [5]Kunming Police Dog Base,Ministry of Public Security,Kunming 650204,China [6]Laboratory for Conservation and Utilization of Bio-resource&Key Laboratory for Microbial Resources of the Ministry of Education,Yunnan University,Kunming 650091,China [7]Center for Excellence in Brain Science and Intelligence Technology,Chinese Academy of Sciences,Shanghai 200031,China [8]KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases,Kunming Institute of Zoology,Chinese Academy of Sciences,Kunming 650223,China [9]Center for Excellence in Animal Evolution and Genetics,Chinese Academy of Sciences,Kunming 650223,China

出　　处：《Science Bulletin》2021年第2期187-196,M0004,共11页科学通报（英文版）

基　　金：supported by the National Key Research and Development Program of China(2019YFA0707101);the Key Research Program of Frontier Sciences of the Chinese Academy of Sciences(2019YFA0707101);the Innovative Research Team(in Science and Technology)of Yunnan Province(201905E160019);the National Natural Science Foundation of China(81860255,31701133,81722019,and 31201712);Yunnan Applied Basic Research Projects for Kunming Medicine University Special Fund(2017FE468(-134));the Animal Branch of the Germplasm Bank of Wild Species,Chinese Academy of Sciences(the Large Research Infrastructure Funding);supported by the National Youth Talent Support Program;supported by the Hundred-Talent Program of Kunming Medical University。

摘　　要：Obsessive-compulsive disorder(OCD)represents a heterogeneous collection of diseases with diverse levels of phenotypic,genetic,and etiologic variability,making it difficult to identify the underlying genetic and biological mechanisms in humans.Domestic dogs exhibit several OCD-like behaviors.Using continuous circling as a representative phenotype for OCD,we screened two independent dog breeds,the Belgian Malinois and Kunming Dog and subsequently sequenced ten circling dogs and ten unaffected dogs for each breed.Using population differentiation analyses,we identified 11 candidate genes in the extreme tail of the differentiated regions between cases and controls.These genes overlap significantly with genes identified in a genome wide association study(GWAS)of human OCD,indicating strong convergence between humans and dogs.Through gene expressional analysis and functional exploration,we found that two candidate OCD risk genes,PPP2R2B and ADAMTSL3,affected the density and morphology of dendritic spines.Therefore,changes in dendritic spine may underlie some common biological and physiological pathways shared between humans and dogs.Our study revealed an unprecedented level of convergence in OCD shared between humans and dogs,and highlighted the importance of using domestic dogs as a model species for many human diseases including OCD.强迫症是一种异质性极高的精神疾病,人类群体中探索其潜在生物学机制异常困难.家犬作为最早驯化的一种家养动物,自发强迫症,且与人类强迫症具有多种相似表型.因此,开展家犬强迫症的遗传和细胞学研究将有助于阐明两者强迫症共享的生物学机制.本研究针对转圈行为这一家犬强迫症的代表性表型,在两个独立犬种中(比利时马里努阿犬和昆明犬)开展了表型鉴定和全基因组测序工作.通过群体分化和全基因组关联分析筛选到11个候选强迫症风险基因,其与人类全基因组关联研究揭示的强迫症关联基因有显著重叠(P<0.0001),证实了人类和家犬强迫症的显著遗传趋同性.进一步的基因表达分析和功能验证表明两个强迫症候选风险基因PPP2R2B和ADAMTSL3显著影响树突棘的发育、密度和形态,提示树突棘发育与功能改变可能是强迫症发病的潜在机制.该研究揭示了人和家犬强迫症在遗传和细胞生物学方面的趋同性,提示家犬或可作为人类疾病研究的模型物种.

关 键 词：Obsessive-compulsive disorder Circling behavior Whole genome sequencing Genetic convergence Domestic dogs 

分 类 号：R749.7[医药卫生—神经病学与精神病学]