Candidate genes and functional noncoding variants identified in a canine model of obsessive-compulsive disorder.
Candidate genes and functional noncoding variants identified in a canine model of obsessive-compulsive disorder.
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DOI：
10.1186/gb-2014-15-3-r25
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发表时间：
2014-03-14
期刊：
影响因子：
12.3
通讯作者：
Karlsson EK
中科院分区：
文献类型：
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作者：
Tang R;Noh HJ;Wang D;Sigurdsson S;Swofford R;Perloski M;Duxbury M;Patterson EE;Albright J;Castelhano M;Auton A;Boyko AR;Feng G;Lindblad-Toh K;Karlsson EK
强迫症(OCD)是一种严重的精神疾病，表现为耗时重复的行为，影响1%至3%的人类人口。虽然高度可遗传，但复杂的遗传学阻碍了阐明强迫症病因的努力。狗患有自然发生的强迫症，与人类强迫症非常相似，表现为过度重复正常的犬类行为，对药物治疗只有部分反应。狗品种的有限多样性使得识别潜在的遗传因素变得更容易。我们使用87个杜宾犬病例和63个对照的全基因组关联来识别与强迫症相关的基因组基因座，并在8个高危品种和8个品种匹配的对照犬中对这些区域进行测序。我们在进化上保守的位置发现了119个变异，这些变异是强迫症狗特有的。与没有已知精神问题的品种相比，这些仅有病例的变异在强迫症高危品种中明显更常见。有四个基因都具有突触功能，具有最大的病例变异：神经元钙粘蛋白(CDH2)、连环素α2(CTNNA2)、ataxin-1(ATXN1)和血浆谷氨酸羧基肽酶(PGCP)。在钙粘素基因CDH2和DSC3之间的2个Mb基因沙漠中，我们发现了两个不同的变体，它们只在强迫症犬身上发现，它们扰乱了相同的高度保守的调控元件。这些变异导致人类神经母细胞瘤细胞系的基因表达发生显著变化，可能是由于转录因子结合中断所致。狗品种有限的遗传多样性有助于识别狗和人类在机械上相似的复杂精神疾病背后的基因、功能变异和调控途径。
Obsessive-compulsive disorder (OCD), a severe mental disease manifested in time-consuming repetition of behaviors, affects 1 to 3% of the human population. While highly heritable, complex genetics has hampered attempts to elucidate OCD etiology. Dogs suffer from naturally occurring compulsive disorders that closely model human OCD, manifested as an excessive repetition of normal canine behaviors that only partially responds to drug therapy. The limited diversity within dog breeds makes identifying underlying genetic factors easier. We use genome-wide association of 87 Doberman Pinscher cases and 63 controls to identify genomic loci associated with OCD and sequence these regions in 8 affected dogs from high-risk breeds and 8 breed-matched controls. We find 119 variants in evolutionarily conserved sites that are specific to dogs with OCD. These case-only variants are significantly more common in high OCD risk breeds compared to breeds with no known psychiatric problems. Four genes, all with synaptic function, have the most case-only variation: neuronal cadherin (CDH2), catenin alpha2 (CTNNA2), ataxin-1 (ATXN1), and plasma glutamate carboxypeptidase (PGCP). In the 2 Mb gene desert between the cadherin genes CDH2 and DSC3, we find two different variants found only in dogs with OCD that disrupt the same highly conserved regulatory element. These variants cause significant changes in gene expression in a human neuroblastoma cell line, likely due to disrupted transcription factor binding. The limited genetic diversity of dog breeds facilitates identification of genes, functional variants and regulatory pathways underlying complex psychiatric disorders that are mechanistically similar in dogs and humans.
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影响因子：
9.8
作者：
Boyko AR;Quignon P;Li L;Schoenebeck JJ;Degenhardt JD;Lohmueller KE;Zhao K;Brisbin A;Parker HG;vonHoldt BM;Cargill M;Auton A;Reynolds A;Elkahloun AG;Castelhano M;Mosher DS;Sutter NB;Johnson GS;Novembre J;Hubisz MJ;Siepel A;Wayne RK;Bustamante CD;Ostrander EA
通讯作者：
Ostrander EA
影响因子：
12.3
作者：
Karlsson EK;Sigurdsson S;Ivansson E;Thomas R;Elvers I;Wright J;Howald C;Tonomura N;Perloski M;Swofford R;Biagi T;Fryc S;Anderson N;Courtay-Cahen C;Youell L;Ricketts SL;Mandlebaum S;Rivera P;von Euler H;Kisseberth WC;London CA;Lander ES;Couto G;Comstock K;Starkey MP;Modiano JF;Breen M;Lindblad-Toh K
通讯作者：
Lindblad-Toh K
影响因子：
1.4
作者：
Laks, Jerson;Fontenelle, Leonardo F.;Mendlowicz, Mauro V.
通讯作者：
Mendlowicz, Mauro V.
影响因子：
3.6
作者：
Barth, Mareike;Rickelt, Steffen;Franke, Werner Wilhelm
通讯作者：
Franke, Werner Wilhelm
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
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