Molecular and Genetic Characterization of Depression: Overlap with other Psychiatric Disorders and Aging.
Molecular and Genetic Characterization of Depression: Overlap with other Psychiatric Disorders and Aging.
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DOI：
10.1159/000369974
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发表时间：
2015-05
期刊：
影响因子：
--
通讯作者：
Sibille E
中科院分区：
文献类型：
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作者：
Ding Y;Chang LC;Wang X;Guilloux JP;Parrish J;Oh H;French BJ;Lewis DA;Tseng GC;Sibille E
全基因组表达和基因分型技术以前所未有的速度揭示了复杂疾病的遗传基础;然而，尽管重性抑郁症（MDD）负担沉重且患病率高，但其分子特征却相对滞后。转录组研究报告了多种脑干扰，但受样本量小的限制。全基因组关联研究（GWAS）报告了弱结果，但表明与其他神经精神疾病重叠的遗传风险。我们进行了系统的分子特征的改变，在MDD的脑功能，在101名受试者的三个皮质边缘脑区的8个基因阵列研究的差异表达的荟萃分析。鉴定的“metaA-MDD”基因表明MDD中神经营养支持、脑可塑性和神经元信号传导改变。值得注意的是，MetaA-MDD基因在共表达网络中显示出低连接性和中心性，以及均匀的基因组分布，与弥散性多基因机制一致。接下来，我们将这些发现与1800多个已发表的GWAS的结果进行了整合，并表明MetaA-MDD基因附近的遗传变异预测神经精神疾病的风险更大，特别是与年龄相关的表型，但不适用于其他医学疾病，包括那些经常与抑郁症或身体特征共病的疾病。总的来说，基因功能（转录组）和结构（GWAS）的无偏研究的交叉点为研究MDD的分子机制提供了新的线索，并提出了抑郁症，其他神经精神疾病和脑老化之间的共同生物学途径。
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 overlapping genetic risk with other neuropsychiatric disorders. We performed systematic molecular characterization of altered brain function in MDD, using meta-analysis of differential expression in eight gene array studies in three 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 low connectivity and hubness in coexpression networks, and uniform genomic distribution, consistent with diffuse polygenic mechanisms. We next integrated these findings with results from over 1800 published GWAS and show that genetic variations nearby metaA-MDD genes predict greater risk for neuropsychiatric disorders and notably for age-related phenotypes, but not for other medical illnesses, including those frequently co-morbid 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 suggest common biological pathways between depression, other neuropsychiatric diseases, and brain aging.