Foo Jerome C, Streit Fabian, Treutlein Jens, Ripke Stephan, Witt Stephanie H, Strohmaier Jana, Degenhardt Franziska, Forstner Andreas J, Hoffmann Per, Soyka Michael, Dahmen Norbert, Scherbaum Norbert, Wodarz Norbert, Heilmann-Heimbach Stefanie, Herms Stefan, Cichon Sven, Preuss Ulrich, Gaebel Wolfgang, Ridinger Monika, Hoffmann Sabine, Schulze Thomas G, Maier Wolfgang, Zill Peter, Müller-Myhsok Bertram, Ising Marcus, Lucae Susanne, Nöthen Markus M, Mann Karl, Kiefer Falk, Rietschel Marcella, Frank Josef
Central Institute of Mental Health, Department of Genetic Epidemiology in Psychiatry, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, US.
Psychiatr Genet. 2018 Aug;28(4):66-70. doi: 10.1097/YPG.0000000000000201.
The clinical comorbidity of alcohol dependence (AD) and major depressive disorder (MDD) is well established, whereas genetic factors influencing co-occurrence remain unclear. A recent study using polygenic risk scores (PRS) calculated based on the first-wave Psychiatric Genomics Consortium MDD meta-analysis (PGC-MDD1) suggests a modest shared genetic contribution to MDD and AD. Using a (~10 fold) larger discovery sample, we calculated PRS based on the second wave (PGC-MDD2) of results, in a severe AD case–control target sample. We found significant associations between AD disease status and MDD-PRS derived from both PGC-MDD2 (most informative P-threshold=1.0, P=0.00063, R2=0.533%) and PGC-MDD1 (P-threshold=0.2, P=0.00014, R2=0.663%) meta-analyses; the larger discovery sample did not yield additional predictive power. In contrast, calculating PRS in a MDD target sample yielded increased power when using PGC-MDD2 (P-threshold=1.0, P=0.000038, R2=1.34%) versus PGC-MDD1 (P-threshold=1.0, P=0.0013, R2=0.81%). Furthermore, when calculating PGC-MDD2 PRS in a subsample of patients with AD recruited explicitly excluding comorbid MDD, significant associations were still found (n=331; P-threshold=1.0, P=0.042, R2=0.398%). Meanwhile, in the subset of patients in which MDD was not the explicit exclusion criteria, PRS predicted more variance (n=999; P-threshold=1.0, P=0.0003, R2=0.693%). Our findings replicate the reported genetic overlap between AD and MDD and also suggest the need for improved, rigorous phenotyping to identify true shared cross-disorder genetic factors. Larger target samples are needed to reduce noise and take advantage of increasing discovery sample size.
酒精依赖（AD）与重度抑郁症（MDD）的临床共病现象已得到充分证实，然而，影响二者共现的遗传因素仍不明确。最近一项研究使用基于首轮精神病基因组学联盟重度抑郁症荟萃分析（PGC-MDD1）计算的多基因风险评分（PRS），表明重度抑郁症和酒精依赖存在适度的共同遗传贡献。我们使用一个（约10倍）更大的发现样本，在一个重度酒精依赖病例对照目标样本中，基于第二轮（PGC-MDD2）结果计算了PRS。我们发现，酒精依赖疾病状态与源自PGC-MDD2（最具信息量的P值阈值 = 1.0，P = 0.00063，R2 = 0.533%）和PGC-MDD1（P值阈值 = 0.2，P = 0.00014，R2 = 0.663%）荟萃分析的重度抑郁症PRS之间存在显著关联；更大的发现样本并未产生额外的预测能力。相比之下，在重度抑郁症目标样本中计算PRS时，使用PGC-MDD2（P值阈值 = 1.0，P = 0.000038，R2 = 1.34%）比使用PGC-MDD1（P值阈值 = 1.0，P = 0.0013，R2 = 0.81%）具有更强的预测能力。此外，在明确排除共病重度抑郁症的酒精依赖患者亚样本中计算PGC-MDD2 PRS时，仍发现显著关联（n = 331；P值阈值 = 1.0，P = 0.042，R2 = 0.398%）。同时，在未将重度抑郁症作为明确排除标准的患者子集中，PRS预测的方差更大（n = 999；P值阈值 = 1.0，P = 0.0003，R2 = 0.693%）。我们的研究结果重复了所报道的酒精依赖和重度抑郁症之间的遗传重叠，也表明需要改进、严格的表型分析来识别真正的跨疾病共享遗传因素。需要更大的目标样本以减少噪声，并利用不断增加的发现样本量。
