Department of Psychiatry, Yale School of Medicine and VA CT Healthcare Center, West Haven, CT, USA.
Center for Child and Family Traumatic Stress, Kennedy Krieger Institute, Baltimore, MD, USA.
Acta Psychiatr Scand. 2018 Feb;137(2):148-156. doi: 10.1111/acps.12843. Epub 2017 Dec 11.
To investigate whether trauma exposure moderates the genetic correlation between substance use disorders and psychiatric disorders, we tested whether trauma exposure modifies the association of genetic risks for mental disorders with alcohol misuse and nicotine dependence (ND) symptoms.
High-resolution polygenic risk scores (PRSs) were calculated for 10 732 US Army soldiers (8346 trauma-exposed and 2386 trauma-unexposed) based on genome-wide association studies of bipolar disorder (BD), major depressive disorder, and schizophrenia.
The main finding was a significant BD PRS-by-trauma interaction with respect to alcohol misuse (P = 6.07 × 10 ). We observed a positive correlation between BD PRS and alcohol misuse in trauma-exposed soldiers (r = 0.029, P = 7.5 × 10 ) and a negative correlation in trauma-unexposed soldiers (r = -0.071, P = 5.61 × 10 ). Consistent (nominally significant) result with concordant effect, directions were observed in the schizophrenia PRS-by-trauma interaction analysis. The variants included in the BD PRS-by-trauma interaction showed significant enrichments for gene ontologies related to high voltage-gated calcium channel activity (GO:0008331, P = 1.51 × 10 ; GO:1990454, P = 4.49 × 10 ; GO:0030315, P = 2.07 × 10 ) and for Beta1/Beta2 adrenergic receptor signaling pathways (P = 2.61 × 10 ).
These results indicate that the genetic overlap between alcohol misuse and BD is significantly moderated by trauma exposure. This provides molecular insight into the complex mechanisms that link substance abuse, psychiatric disorders, and trauma exposure.
为了研究创伤暴露是否调节物质使用障碍和精神障碍之间的遗传相关性，我们检验了创伤暴露是否改变了精神障碍遗传风险与酒精使用障碍和尼古丁依赖（ND）症状之间的关联。
根据双相情感障碍（BD）、重度抑郁症和精神分裂症的全基因组关联研究，为 10732 名美国陆军士兵（8346 名创伤暴露和 2386 名创伤未暴露）计算了高分辨率多基因风险评分（PRS）。
主要发现是 BD PRS 与创伤之间存在显著的相互作用，与酒精使用障碍有关（P=6.07×10）。我们观察到，在创伤暴露的士兵中，BD PRS 与酒精使用障碍呈正相关（r=0.029，P=7.5×10），而在未暴露的士兵中则呈负相关（r=-0.071，P=5.61×10）。在精神分裂症 PRS 与创伤相互作用的分析中，观察到了一致的（名义上显著的）结果，方向一致。包括在 BD PRS 与创伤相互作用中的变异显示出与高电压门控钙通道活性相关的基因本体论的显著富集（GO：0008331，P=1.51×10；GO：1990454，P=4.49×10；GO：0030315，P=2.07×10）和 Beta1/Beta2 肾上腺素能受体信号通路（P=2.61×10）。
这些结果表明，酒精使用障碍和 BD 之间的遗传重叠显著受创伤暴露的调节。这为物质滥用、精神障碍和创伤暴露之间的复杂机制提供了分子上的理解。
