Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California; Department of Genetics, Stanford University School of Medicine, Stanford, California.
Department of Biological Psychology, Amsterdam Public Health Research Institute, Amsterdam, the Netherlands; Department of Psychiatry, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
Biol Psychiatry. 2019 Jun 15;85(12):1065-1073. doi: 10.1016/j.biopsych.2019.02.022. Epub 2019 Mar 13.
Major depressive disorder (MDD) is moderately heritable, with a high prevalence and a presumed high heterogeneity. Copy number variants (CNVs) could contribute to the heritable component of risk, but the two previous genome-wide association studies of rare CNVs did not report significant findings.
In this meta-analysis of four cohorts (5780 patients and 6626 control subjects), we analyzed the association of MDD to 1) genome-wide burden of rare deletions and duplications, partitioned by length (<100 kb or >100 kb) and other characteristics, and 2) individual rare exonic CNVs and CNV regions.
Patients with MDD carried significantly more short deletions than control subjects (p = .0059) but not long deletions or short or long duplications. The confidence interval for long deletions overlapped with that for short deletions, but long deletions were 70% less frequent genome-wide, reducing the power to detect increased burden. The increased burden of short deletions was primarily in intergenic regions. Short deletions in cases were also modestly enriched for high-confidence enhancer regions. No individual CNV achieved thresholds for suggestive or significant association after genome-wide correction. p values < .01 were observed for 15q11.2 duplications (TUBGCP5, CYFIP1, NIPA1, and NIPA2), deletions in or near PRKN or MSR1, and exonic duplications of ATG5.
The increased burden of short deletions in patients with MDD suggests that rare CNVs increase the risk of MDD by disrupting regulatory regions. Results for longer deletions were less clear, but no large effects were observed for long multigenic CNVs (as seen in schizophrenia and autism). Further studies with larger sample sizes are warranted.
重度抑郁症（MDD）具有中度遗传性，其患病率高且存在明显的异质性。拷贝数变异（CNVs）可能是导致风险遗传成分的原因之一，但之前两项关于罕见 CNVs 的全基因组关联研究并未报告显著结果。
在对四个队列（5780 名患者和 6626 名对照）进行的荟萃分析中，我们分析了 MDD 与以下因素的关联：1）罕见缺失和重复的全基因组负担，按长度（<100 kb 或>100 kb）和其他特征划分；2）个体罕见外显子 CNVs 和 CNV 区域。
MDD 患者携带的短缺失明显多于对照（p=0.0059），但长缺失或短或长重复则不然。长缺失的置信区间与短缺失的置信区间重叠，但长缺失在全基因组范围内的频率低 70%，降低了检测负担增加的能力。短缺失的增加负担主要在基因间区域。病例中的短缺失也适度富集了高置信度增强子区域。经过全基因组校正后，没有个体 CNV 达到提示或显著关联的阈值。在 15q11.2 重复（TUBGCP5、CYFIP1、NIPA1 和 NIPA2）、PRKN 或 MSR1 附近或内部缺失以及 ATG5 外显子重复中观察到 p 值<.01。
MDD 患者中短缺失的负担增加表明，罕见 CNVs 通过破坏调节区域增加了 MDD 的风险。较长缺失的结果不太明确，但未观察到长多基因 CNVs（如在精神分裂症和自闭症中所见）的大效应。需要更大样本量的进一步研究。
