McLean Hospital, Belmont, Massachusetts, USA.
Am J Med Genet B Neuropsychiatr Genet. 2013 Jun;162B(4):367-79. doi: 10.1002/ajmg.b.32137. Epub 2013 Apr 18.
The neuronal glutamate transporter gene SLC1A1 is a candidate gene for obsessive-compulsive disorder (OCD) based on linkage studies and convergent evidence implicating glutamate in OCD etiology. The 3' end of SLC1A1 is the only genomic region with consistently demonstrated OCD association, especially when analyzing male-only probands. However, specific allele associations have not been consistently replicated, and recent OCD genome-wide association and meta-analysis studies have not incorporated all previously associated SLC1A1 SNPs. To clarify the nature of association between SLC1A1 and OCD, pooled analysis was performed on all available relevant raw study data, comprising a final sample of 815 trios, 306 cases and 634 controls. This revealed weak association between OCD and one of nine tested SLC1A1 polymorphisms (rs301443; uncorrected P = 0.046; non-significant corrected P). Secondary analyses of male-affecteds only (N = 358 trios and 133 cases) demonstrated modest association between OCD and a different SNP (rs12682807; uncorrected P = 0.012; non-significant corrected P). Findings of this meta-analysis are consistent with the trend of previous candidate gene studies in psychiatry and do not clarify the putative role of SLC1A1 in OCD pathophysiology. Nonetheless, it may be important to further examine the potential associations demonstrated in this amalgamated sample, especially since the SNPs with modest associations were not included in the more highly powered recent GWAS or in a past meta-analysis including five SLC1A1 polymorphisms. This study underscores the need for much larger sample sizes in future genetic association studies and suggests that next-generation sequencing may be beneficial in examining the potential role of rare variants in OCD.
神经元谷氨酸转运体基因 SLC1A1 是强迫症 (OCD) 的候选基因，这基于连锁研究和汇聚证据表明谷氨酸在 OCD 发病机制中的作用。SLC1A1 的 3' 末端是唯一一致显示 OCD 关联的基因组区域，特别是在分析仅男性先证者时。然而，特定等位基因的关联尚未得到一致复制，最近的 OCD 全基因组关联和荟萃分析研究并未纳入所有先前关联的 SLC1A1 SNPs。为了阐明 SLC1A1 与 OCD 之间的关联性质，对所有可用的相关原始研究数据进行了汇总分析，最终样本包括 815 个三核苷酸、306 个病例和 634 个对照。这表明 OCD 与九种测试的 SLC1A1 多态性之一(rs301443；未校正 P=0.046；校正后非显著 P)之间存在弱关联。仅对男性受影响者进行的二次分析(n=358 个三核苷酸和 133 个病例)表明，OCD 与另一个 SNP(rs12682807；未校正 P=0.012；校正后非显著 P)之间存在中度关联。这项荟萃分析的结果与精神病学以前候选基因研究的趋势一致，并没有阐明 SLC1A1 在 OCD 病理生理学中的潜在作用。尽管如此，进一步检查这个混合样本中显示的潜在关联可能很重要，特别是因为具有中度关联的 SNP 未包含在最近的 GWAS 或包括五个 SLC1A1 多态性的过去荟萃分析中。这项研究强调了在未来的遗传关联研究中需要更大的样本量，并表明下一代测序可能有助于检查 OCD 中罕见变异的潜在作用。
