A haplotype containing quantitative trait loci for SLC1A1 gene expression and its association with obsessive-compulsive disorder.
A haplotype containing quantitative trait loci for SLC1A1 gene expression and its association with obsessive-compulsive disorder.
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DOI：
10.1001/archgenpsychiatry.2009.6
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发表时间：
2009-04
影响因子：
--
通讯作者：
Murphy, Dennis L.
中科院分区：
文献类型：
--
作者：
Wendland, Jens R.;Moya, Pablo R.;Timpano, Kiara R.;Anavitarte, Adriana P.;Kruse, Matthew R.;Wheaton, Michael G.;Ren-Patterson, Renee F.;Murphy, Dennis L.
最近的连锁分析和后续候选基因研究的证据支持参与SLC 1A 1，它编码的神经元谷氨酸转运蛋白，在强迫症（OCD）的发展。在一项大型病例对照研究中确定SLC 1A 1基因变异在强迫症中的作用，并更好地了解SLC 1A 1变异如何影响功能。病例对照研究。公开可获得的SLC 1A 1表达和基因型数据。325名强迫症先证者和662名种族和性别匹配的对照。先证者采用DSM-IV结构化临床访谈、耶鲁-布朗强迫量表和储蓄量表修订版进行评估。六个单核苷酸多态性（SNPs）进行基因分型。通过排列进行单标记和单倍型分析的多重检验校正。SLC 1A 1的基因表达在淋巴母细胞系中是可遗传的。我们在SLC 1A 1中或附近发现了3个与基因表达水平相关的SNP，其中1个先前与OCD相关。其中两个SNP还预测了人脑组织中的表达水平，1个SNP在报告基因研究中进一步发挥作用。在3个SNPs，rs3087879，rs301430，和rs7858819，两个单倍型与强迫症显着相关的多重检验校正后，包含2个SNPs与表达水平。此外，另一个与SLC 1A 1基因表达相关的SNP rs3933331与OCD囤积亚表型相关，通过2个独立的验证量表进行评估。我们的病例对照数据证实了以前较小的以家庭为基础的研究，表明SLC 1A 1是强迫症的易感位点。我们使用的表达和基因型数据库挖掘方法提供了一个潜在的有用的补充方法，以加强未来的候选基因在神经精神和其他疾病的研究。
Recent evidence from linkage analyses and follow-up candidate gene studies supports the involvement of SLC1A1, which encodes the neuronal glutamate transporter, in the development of obsessive-compulsive disorder (OCD). To determine the role of genetic variation of SLC1A1 in OCD in a large case-control study and to better understand how SLC1A1 variation affects functionality. A case-control study. Publicly accessible SLC1A1 expression and genotype data. Three hundred twenty-five OCD probands and 662 ethnically and sex-matched controls. Probands were assessed with the Structured Clinical Interview for DSM-IV, the Yale-Brown Obsessive Compulsive Scale, and the Saving Inventory–Revised. Six single-nucleotide polymorphisms (SNPs) were genotyped. Multiple testing corrections for single-marker and haplotype analyses were performed by permutation. Gene expression of SLC1A1 is heritable in lymphoblastoid cell lines. We identified 3 SNPs in or near SLC1A1 that correlated with gene expression levels, 1 of which had previously been associated with OCD. Two of these SNPs also predicted expression levels in human brain tissue, and 1 SNP was further functional in reporter gene studies. Two haplotypes at 3 SNPs, rs3087879, rs301430, and rs7858819, were significantly associated with OCD after multiple-testing correction and contained 2 SNPs associated with expression levels. In addition, another SNP correlating with SLC1A1 gene expression, rs3933331, was associated with an OCD-hoarding subphenotype as assessed by 2 independent, validated scales. Our case-control data corroborate previous smaller family-based studies that indicated that SLC1A1 is a susceptibility locus for OCD. The expression and genotype database–mining approach we used provides a potentially useful complementary approach to strengthen future candidate gene studies in neuropsychiatric and other disorders.
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