Supplementary Material for: Molecular and Genetic Characterization of Depression: Overlap with Other Psychiatric Disorders and Aging

Genome-wide expression and genotyping technologies have uncovered the genetic bases of complex diseases at unprecedented rates. However, despite its heavy burden and high prevalence, the molecular characterization of major depressive disorder (MDD) has lagged behind. Transcriptome studies report multiple brain disturbances but are limited by small sample sizes. Genome-wide association studies (GWAS) report weak results but suggest an overlapping genetic risk with other neuropsychiatric disorders. We performed a systematic molecular characterization of altered brain function in MDD using meta-analysis of differential expression of 8 gene array studies across 3 corticolimbic brain regions in 101 subjects. The identified ‘metaA-MDD' genes suggest altered neurotrophic support, brain plasticity and neuronal signaling in MDD. Notably, metaA-MDD genes display a low connectivity and hubness in coexpression networks as well as a uniform genomic distribution, which is consistent with diffuse polygenic mechanisms. We have integrated these findings with results from over 1,800 published GWAS and show that genetic variations nearby metaA-MDD genes predict a greater risk for neuropsychiatric disorders, and notably for age-related phenotypes, but not for other medical illnesses (including those frequently co-occurring with depression) or body characteristics. Collectively, the intersection of unbiased investigations of gene function (transcriptome) and structure (GWAS) provides novel leads to investigate molecular mechanisms of MDD and suggests common biological pathways between depression, other neuropsychiatric diseases and brain aging.

全基因组表达与基因分型技术正以前所未有的速度揭示复杂疾病的遗传基础。然而，尽管重度抑郁症（Major Depressive Disorder, MDD）负担沉重且患病率居高不下，但其分子特征解析却相对滞后。转录组研究虽已报道了多种大脑功能异常，但受限于样本量较小的问题。全基因组关联研究（Genome-Wide Association Studies, GWAS）虽得出的关联结果较弱，但提示其与其他神经精神疾病存在重叠的遗传风险。本研究针对101名受试者的3个皮质边缘脑区，整合8项基因芯片研究的差异表达数据进行荟萃分析，系统解析了MDD患者大脑功能的异常改变。本次研究鉴定得到的‘metaA-MDD’基因提示，MDD患者体内神经营养支持、大脑可塑性以及神经元信号传导均发生异常。值得注意的是，‘metaA-MDD’基因在共表达网络中呈现出较低的连接度和中心性，且其基因组分布较为均匀，这与弥散性多基因致病机制相符。本研究将上述发现与超过1800项已发表的GWAS结果进行整合，结果显示，‘metaA-MDD’基因附近的遗传变异可预测神经精神疾病（尤其是年龄相关表型）的更高发病风险，但与其他内科疾病（包括与抑郁症常共病的病症）或躯体特征无关。综上，针对基因功能（转录组）与基因结构（GWAS）的无偏研究的交叉分析，为解析MDD的分子机制提供了全新的研究方向，同时也提示抑郁症、其他神经精神疾病与大脑衰老之间存在共同的生物学通路。