John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, United States of America ; Department of Neuroscience, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
PLoS One. 2013 Aug 21;8(8):e70376. doi: 10.1371/journal.pone.0070376. eCollection 2013.
Obsessive compulsive disorder (OCD) is a syndrome characterized by recurrent and intrusive thoughts and ritualistic behaviors or mental acts that a person feels compelled to perform. Twin studies, family studies, and segregation analyses provide compelling evidence that OCD has a strong genetic component. The SLITRK1 gene encodes a developmentally regulated stimulator of neurite outgrowth and previous studies have implicated rare variants in this gene in disorders in the OC spectrum, specifically Tourette syndrome (TS) and trichotillomania (TTM). The objective of the current study was to evaluate rare genetic variation in SLITRK1 in risk for OCD and to functionally characterize associated coding variants. We sequenced SLITRK1 coding exons in 381 individuals with OCD as well as in 356 control samples and identified three novel variants in seven individuals. We found that the combined mutation load in OCD relative to controls was significant (p = 0.036). We identified a missense N400I change in an individual with OCD, which was not found in more than 1000 control samples (P<0.05). In addition, we showed the the N400I variant failed to enhance neurite outgrowth in primary neuronal cultures, in contrast to wildtype SLITRK1, which enhanced neurite outgrowth in this assay. These important functional differences in the N400I variant, as compared to the wildtype SLITRK1 sequence, may contribute to OCD and OC spectrum symptoms. A synonymous L63L change identified in an individual with OCD and an additional missense change, T418S, was found in four individuals with OCD and in one individual without an OCD spectrum disorder. Examination of additional samples will help assess the role of rare SLITRK1 variation in OCD and in related psychiatric illness.
强迫症（OCD）是一种以反复出现和侵入性思维以及仪式性行为或精神行为为特征的综合征，患者感到不得不执行这些行为。双胞胎研究、家族研究和分离分析提供了令人信服的证据表明，OCD 具有很强的遗传成分。SLITRK1 基因编码一种发育调节的神经突生长刺激因子，先前的研究表明该基因中的罕见变异与 OC 谱中的疾病有关，特别是妥瑞氏症（TS）和拔毛癖（TTM）。本研究的目的是评估 SLITRK1 中的罕见遗传变异是否与 OCD 风险相关，并对相关编码变异进行功能特征分析。我们对 381 名 OCD 患者和 356 名对照样本中的 SLITRK1 编码外显子进行了测序，在 7 名个体中发现了 3 个新的变异。我们发现，与对照组相比，OCD 患者的组合突变负荷显著（p=0.036）。我们在一名 OCD 患者中发现了一个错义 N400I 变化，而在 1000 多个对照样本中未发现（P<0.05）。此外，我们表明，与野生型 SLITRK1 相比，N400I 变体未能增强原代神经元培养物中的神经突生长，而野生型 SLITRK1 在该测定中增强了神经突生长。与野生型 SLITRK1 序列相比，N400I 变体在这些重要功能上的差异可能导致 OCD 和 OC 谱症状。在一名 OCD 患者中发现了一个同义 L63L 变化，在四名 OCD 患者和一名无 OCD 谱障碍的患者中发现了另一个错义变化 T418S。对额外样本的检查将有助于评估 SLITRK1 罕见变异在 OCD 和相关精神疾病中的作用。
