Genetic Epidemiology, Molecular Epidemiology, Psychiatric Genetics and Queensland Statistical Genetics Laboratories, Queensland Institute of Medical Research, Brisbane, QLD, Australia.
Mol Psychiatry. 2012 Jan;17(1):36-48. doi: 10.1038/mp.2010.109. Epub 2010 Nov 2.
Major depressive disorder (MDD) is a common complex disorder with a partly genetic etiology. We conducted a genome-wide association study of the MDD2000+ sample (2431 cases, 3673 screened controls and >1 M imputed single-nucleotide polymorphisms (SNPs)). No SNPs achieved genome-wide significance either in the MDD2000+ study, or in meta-analysis with two other studies totaling 5763 cases and 6901 controls. These results imply that common variants of intermediate or large effect do not have main effects in the genetic architecture of MDD. Suggestive but notable results were (a) gene-based tests suggesting roles for adenylate cyclase 3 (ADCY3, 2p23.3) and galanin (GAL, 11q13.3); published functional evidence relates both of these to MDD and serotonergic signaling; (b) support for the bipolar disorder risk variant SNP rs1006737 in CACNA1C (P=0.020, odds ratio=1.10); and (c) lack of support for rs2251219, a SNP identified in a meta-analysis of affective disorder studies (P=0.51). We estimate that sample sizes 1.8- to 2.4-fold greater are needed for association studies of MDD compared with those for schizophrenia to detect variants that explain the same proportion of total variance in liability. Larger study cohorts characterized for genetic and environmental risk factors accumulated prospectively are likely to be needed to dissect more fully the etiology of MDD.
重度抑郁症（MDD）是一种常见的复杂疾病，部分病因与遗传有关。我们对 MDD2000+ 样本（2431 例病例、3673 例筛查对照和>100 万经推断的单核苷酸多态性（SNP））进行了全基因组关联研究。在 MDD2000+ 研究中，没有任何 SNP 达到全基因组显著水平，与另外两项共包含 5763 例病例和 6901 例对照的研究的荟萃分析也没有达到全基因组显著水平。这些结果表明，常见的中等或较大效应的变体在 MDD 的遗传结构中没有主要作用。有一些提示性但值得注意的结果，包括：（a）基于基因的测试表明，腺苷酸环化酶 3（ADCY3，2p23.3）和甘丙肽（GAL，11q13.3）可能发挥作用；已发表的功能证据表明这两种基因都与 MDD 和血清素信号有关；（b）支持双相情感障碍风险变异 SNPrs1006737 在 CACNA1C 中的作用（P=0.020，优势比=1.10）；（c）rs2251219 缺乏支持，该 SNP 是在情感障碍研究的荟萃分析中发现的（P=0.51）。我们估计，与精神分裂症相比，MDD 的关联研究需要增加 1.8 到 2.4 倍的样本量，才能检测到能解释相同比例的总发病风险的变异。为了更全面地解析 MDD 的病因，可能需要前瞻性地积累具有遗传和环境风险因素的更大的研究队列。
