Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
PLoS One. 2010 Dec 1;5(12):e15463. doi: 10.1371/journal.pone.0015463.
Major depressive disorder (MDD) is a common psychiatric and behavioral disorder. To discover novel variants conferring risk to MDD, we conducted a whole-genome scan of copy number variation (CNV), including 1,693 MDD cases and 4,506 controls genotyped on the Perlegen 600K platform. The most significant locus was observed on 5q35.1, harboring the SLIT3 gene (P = 2×10(-3)). Extending the controls with 30,000 subjects typed on the Illumina 550 k array, we found the CNV to remain exclusive to MDD cases (P = 3.2×10(-9)). Duplication was observed in 5 unrelated MDD cases encompassing 646 kb with highly similar breakpoints. SLIT3 is integral to repulsive axon guidance based on binding to Roundabout receptors. Duplication of 5q35.1 is a highly penetrant variation accounting for 0.7% of the subset of 647 cases harboring large CNVs, using a threshold of a minimum of 10 SNPs and 100 kb. This study leverages a large dataset of MDD cases and controls for the analysis of CNVs with matched platform and ethnicity. SLIT3 duplication is a novel association which explains a definitive proportion of the largely unknown etiology of MDD.
重度抑郁症（MDD）是一种常见的精神和行为障碍。为了发现可能导致 MDD 的新变体，我们对包括 1693 例 MDD 病例和 4506 例对照在内的拷贝数变异（CNV）进行了全基因组扫描，这些病例和对照是在 Perlegen 600K 平台上进行基因分型的。最显著的位置在 5q35.1 上，包含 SLIT3 基因（P=2×10(-3)）。通过对 Illumina 550 k 阵列上的 30000 个对照进行扩展，我们发现该 CNV 仅存在于 MDD 病例中（P=3.2×10(-9)）。在 5 个无关的 MDD 病例中观察到包含 646 kb 的重复，其断点高度相似。SLIT3 通过与 Roundabout 受体结合，是排斥性轴突导向的重要组成部分。5q35.1 的重复是一种高穿透性变异，占携带大 CNV 的 647 例病例子集的 0.7%，使用的阈值为至少 10 个 SNP 和 100 kb。本研究利用大量 MDD 病例和对照的数据集，对具有匹配平台和种族的 CNV 进行了分析。SLIT3 重复是一种新的关联，它解释了 MDD 大部分未知病因的明确比例。
