Accumulating evidence suggests that genetic factors have a role in major depressive disorder (MDD). However, only limited MDD risk loci have been identified so far. Here we perform a meta-analysis (a total of 90,150 MDD cases and 246,603 controls) through combing three genome-wide association studies of MDD, including 23andMe (cases were self-reported with a clinical diagnosis or treatment of depression), CONVERGE (cases were diagnosed using the Composite International Diagnostic Interview) and PGC (cases were diagnosed using direct structured diagnostic interview (by trained interviewers) or clinician-administered DSM-IV checklists). Genetic variants from two previously unreported loci (rs10457592 on 6q16.2 and rs2004910 on 12q24.31) showed significant associations with MDD (P < 5 × 10^-8) in a total of 336,753 subjects. SNPs (a total of 171) with a P < 1 × 10^-7 in the meta-analysis were further replicated in an independent sample (GS:SFHS, 2,659 MDD cases (diagnosed with DSM-IV) and 17,237 controls) and one additional risk locus (rs3785234 on 16p13.3, P = 1.57 × 10^-8) was identified in the combined samples (a total of 92,809 cases and 263,840 controls). Risk variants on the identified risk loci were associated with gene expression in human brain tissues and mRNA expression analysis showed that FBXL4 and RSRC1 were significantly upregulated in brains of MDD cases compared with controls, suggesting that genetic variants may confer risk of MDD through regulating the expression of these two genes. Our study identified three novel risk loci (6q16.2, 12q24.31, and 16p13.3) for MDD and suggested that FBXL4 and RSRC1 may play a role in MDD. Further functional characterization of the identified risk genes may provide new insights for MDD pathogenesis.

中文翻译：

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6q16.2、12q24.31 和 16p13.3 上的常见变异与重度抑郁症有关。

越来越多的证据表明，遗传因素在重度抑郁症 (MDD) 中起作用。然而，到目前为止，仅确定了有限的 MDD 风险位点。在这里，我们通过结合 MDD 的三项全基因组关联研究进行荟萃分析（总共 90,150 例 MDD 病例和 246,603 例对照），包括 23andMe（病例自我报告有抑郁症的临床诊断或治疗）、CONVERGE（病例使用复合国际诊断访谈进行诊断）和 PGC（使用直接结构化诊断访谈（由训练有素的访谈者）或临床医生管理的 DSM-IV 检查表诊断病例）。来自两个先前未报道的基因座的遗传变异（6q16.2 上的 rs10457592 和 12q24.31 上的 rs2004910）显示与 MDD 显着相关（P < 5 × 10 ^-8) 共有 336,753 个科目。将荟萃分析中P < 1 × 10 ^-7的 SNP（总共 171 个）进一步复制到独立样本（GS:SFHS、2,659 例 MDD 病例（诊断为 DSM-IV）和 17,237 例对照）和另外一个风险位点 (rs3785234 on 16p13.3, P = 1.57 × 10 ^-8) 在组合样本中被确定（总共 92,809 例病例和 263,840 例对照）。已识别的风险位点上的风险变异与人脑组织中的基因表达相关，mRNA 表达分析显示，与对照组相比，MDD 病例的大脑中 FBXL4 和 RSRC1 显着上调，表明遗传变异可能通过调节表达来赋予 MDD 风险这两个基因中。我们的研究确定了 MDD 的三个新风险位点（6q16.2、12q24.31 和 16p13.3），并表明 FBXL4 和 RSRC1 可能在 MDD 中发挥作用。确定的风险基因的进一步功能表征可能为 MDD 发病机制提供新的见解。