Bienvenu O J, Wang Y, Shugart Y Y, Welch J M, Grados M A, Fyer A J, Rauch S L, McCracken J T, Rasmussen S A, Murphy D L, Cullen B, Valle D, Hoehn-Saric R, Greenberg B D, Pinto A, Knowles J A, Piacentini J, Pauls D L, Liang K Y, Willour V L, Riddle M, Samuels J F, Feng G, Nestadt G
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
Am J Med Genet B Neuropsychiatr Genet. 2009 Jul 5;150B(5):710-20. doi: 10.1002/ajmg.b.30897.
SAP90/PSD95-associated protein (SAPAP) family proteins are post-synaptic density (PSD) components that interact with other proteins to form a key scaffolding complex at excitatory (glutamatergic) synapses. A recent study found that mice with a deletion of the Sapap3 gene groomed themselves excessively, exhibited increased anxiety-like behaviors, and had cortico-striatal synaptic defects, all of which were preventable with lentiviral-mediated expression of Sapap3 in the striatum; the behavioral abnormalities were also reversible with fluoxetine. In the current study, we sought to determine whether variation within the human Sapap3 gene was associated with grooming disorders (GDs: pathologic nail biting, pathologic skin picking, and/or trichotillomania) and/or obsessive-compulsive disorder (OCD) in 383 families thoroughly phenotyped for OCD genetic studies. We conducted family-based association analyses using the FBAT and GenAssoc statistical packages. Thirty-two percent of the 1,618 participants met criteria for a GD, and 65% met criteria for OCD. Four of six SNPs were nominally associated (P < 0.05) with at least one GD (genotypic relative risks: 1.6-3.3), and all three haplotypes were nominally associated with at least one GD (permuted P < 0.05). None of the SNPs or haplotypes were significantly associated with OCD itself. We conclude that Sapap3 is a promising functional candidate gene for human GDs, though further work is necessary to confirm this preliminary evidence of association.
与SAP90/PSD95相关的蛋白（SAPAP）家族蛋白是突触后致密区（PSD）的组成成分，它们与其他蛋白相互作用，在兴奋性（谷氨酸能）突触处形成关键的支架复合物。最近的一项研究发现，缺失Sapap3基因的小鼠会过度梳理自己，表现出焦虑样行为增加，并且存在皮质-纹状体突触缺陷，而通过慢病毒介导在纹状体中表达Sapap3，所有这些情况都是可以预防的；行为异常用氟西汀治疗也可逆转。在本研究中，我们试图确定人类Sapap3基因内的变异是否与383个为强迫症基因研究进行了全面表型分析的家庭中的梳理障碍（GDs：病理性咬指甲、病理性皮肤搔抓和/或拔毛癖）和/或强迫症（OCD）相关。我们使用FBAT和GenAssoc统计软件包进行了基于家系的关联分析。1618名参与者中有32%符合GD的标准，65%符合OCD的标准。六个单核苷酸多态性（SNP）中的四个与至少一种GD存在名义上的关联（P < 0.05，基因型相对风险：1.6 - 3.3），并且所有三种单倍型均与至少一种GD存在名义上的关联（置换P < 0.05）。没有一个SNP或单倍型与OCD本身存在显著关联。我们得出结论，Sapap3是人类GDs一个有前景的功能候选基因，不过需要进一步的研究来证实这种初步的关联证据。
