Whole Exome Sequencing Identifies a Novel Predisposing Gene, MAPKAP1, for Familial Mixed Mood Disorder
Whole Exome Sequencing Identifies a Novel Predisposing Gene, MAPKAP1, for Familial Mixed Mood Disorder
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全外显子组测序鉴定出家族性混合情绪障碍的新易感基因 MAPKAP1
DOI：
10.3389/fgene.2019.00074
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发表时间：
2019
影响因子：
3.7
通讯作者：
Zhang Kerang
中科院分区：
文献类型：
--
作者：
Yang Chunxia;Li Suping;Ma Jack X;Li Yi;Zhang Aixia;Sun Ning;Wang Yanfang;Xu Yong;Zhang Kerang
背景资料：情绪障碍在全球非致命疾病负担原因中排名第七，通常被认为是一种遗传性疾病。然而，尽管心境障碍的全基因组关联研究（GWAS）取得了成功，但仍有相当一部分遗传性尚未被发现。一部分缺失的遗传力可能是由罕见的编码变异分离的家庭丰富的情绪障碍。研究方法：为了识别与情绪障碍分离的新变体，我们对一个多代家庭的基因组DNA进行了全外显子组测序，该家庭有9名成员患有情绪障碍。我们根据与心境障碍的隔离、预测的功能效应和人群中的患病率，优先考虑家族中潜在的因果变异。此外，对于排名靠前的候选变体，我们进行了体内验证，以探索情绪障碍的发病机制。结果：我们确定了26个候选变异，并根据其分离模式和功能注释进行排名。排名第一的变体rs78809014位于MAPKAP 1基因的内含子7。MAPKAP 1在抑郁症患者和抑郁样小鼠腹侧齿状回外周血中的表达水平均显著高于相应对照组。此外，MAPKAP 1的表达水平与抗抑郁反应相关。结论：虽然在家庭中的确切机制仍有待阐明，我们的数据强烈表明一个可能的作用的变体，rs78809014，在调节过程中的MAPKAP 1的表达，从而在家族性情绪障碍的发展。
Background: Mood disorder is ranked seventh among the worldwide causes of non-fatal disease burden and is generally believed to be a heritable disease. However, there is still a substantial portion of the heritability yet to be discovered, despite the success of genome-wide association studies (GWAS) for mood disorder. A proportion of the missing heritability may be accounted for by rare coding variants segregating in families enriched with mood disorder. Methods: To identify novel variants segregating with mood disorder, we performed whole-exome sequencing on genomic DNA for a multigenerational family with nine members affected with mood disorder. We prioritized potential causal variants within the family based on segregation with mood disorder, predicted functional effects, and prevalence in human populations. In addition, for the top-ranked candidate variant, we conducted validation in vivo to explore the pathogenesis of mood disorder. Results: We identified and ranked 26 candidate variants based on their segregation pattern and functional annotations. The top-ranked variant, rs78809014, is located in intron 7 of the MAPKAP1 gene. The expression levels of MAPKAP1 in peripheral blood of both major depression disorder (MDD) patients and depressive-like mice ventral dentate gyrus were significantly higher than that in the corresponding controls. In addition, the expression level of MAPKAP1 were correlated with antidepressant response. Conclusions: Although the exact mechanisms in the family remain to be elucidated, our data strongly indicate a probable role of the variant, rs78809014, in the regulatory process of the expression of MAPKAP1 and thus in the development of mood disorder in familial mood disorder.