The Implicated Roles of Cell Adhesion Molecule 1 (CADM1) Gene and Altered Prefrontal Neuronal Activity in Attention-Deficit/Hyperactivity Disorder: A "Gene-Brain-Behavior Relationship"?
The Implicated Roles of Cell Adhesion Molecule 1 (CADM1) Gene and Altered Prefrontal Neuronal Activity in Attention-Deficit/Hyperactivity Disorder: A "Gene-Brain-Behavior Relationship"?
复制标题
细胞粘附分子 1 (CADM1) 基因和改变的前额神经元活动在注意力缺陷/多动障碍中的隐含作用：“基因-大脑-行为关系”？
DOI：
10.3389/fgene.2019.00882
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发表时间：
2019-09-26
影响因子：
3.7
通讯作者：
Qian, Qiujin
中科院分区：
文献类型：
--
作者：
Jin, Jiali;Liu, Lu;Qian, Qiujin
背景：与细胞黏附通路相关的基因已涉及注意缺陷/多动障碍（ADHD）的遗传结构。由CADM1基因编码的细胞黏附分子1是一种促进细胞黏附的蛋白质，在人类前额叶高度表达。本研究旨在评估CADM1基因型与ADHD、执行功能和局部脑功能的关联。
方法：对1040名ADHD儿童和青少年以及963名对照者的CADM1的10个标签单核苷酸多态性的基因型数据进行病例 - 对照关联分析。进行斯特鲁普颜色 - 文字干扰测试、雷 - 奥斯特里思复杂图形测试和连线测试，分别评估“抑制”、“工作记忆”和“定势转换”。一个子样本（35名ADHD患者与56名对照者）参与了嵌套的影像遗传学研究。采集静息态功能磁共振图像，并获取低频波动幅度均值（mALFF）。
结果：在“单纯ADHD”亚组中检测到rs10891819具有名义上显著的基因型效应（P = 0.008），TT基因型具有保护作用。但该结果经多重检验校正后不显著。在执行功能任务的表现上未发现直接的遗传效应。在针对“整体ADHD”样本的影像遗传学研究中，rs10891819基因型与右侧额上回（rSFG，峰值t = 3.85，校正后P < 0.05）的mALFF改变显著相关。具体而言，在ADHD组和对照组中，T等位基因携带者的mALFF始终高于GG携带者。内表型相关性分析表明，斯特鲁普测试中的“文字干扰时间”（“文字干扰时间”越短表明抑制功能越好）与rSFG中的mALFF之间存在显著负相关（r = -0.29，P = 0.006）。最后，中介分析证实了从“rs10891819基因型（T等位基因携带者）”通过“mALFF（rSFG）”到“抑制（‘文字干扰时间’）”的显著间接效应（索贝尔兹 = -2.47；B = -2.61，95%置信区间为 -0.48至 -4.72；P = 0.009）。
结论：我们的研究提供了初步证据，表明CADM1与前额叶脑活动、抑制功能和ADHD有关，提示CADM1基因存在潜在的“基因 - 脑 - 行为”关系。未来更大样本量的研究可能会对我们的探索性发现所产生的这些假设进行专门检验。
Background: Genes related to cell adhesion pathway have been implicated in the genetic architecture of attention-deficit/hyperactivity disorder (ADHD). Cell adhesion molecule 1, encoded by CADM1 gene, is a protein which facilitates cell adhesion, highly expressed in the human prefrontal lobe. This study aimed to evaluate the association of CADM1 genotype with ADHD, executive function, and regional brain functions.Methods: The genotype data of 10-tag single nucleotide polymorphisms of CADM1 for 1,040 children and adolescents with ADHD and 963 controls were used for case-control association analyses. Stroop color-word interference test, Rey-Osterrieth complex figure test, and trail making test were conducted to assess "inhibition," "working memory," and "set-shifting," respectively. A subsample (35 ADHD versus 56 controls) participated in the nested imaging genetic study. Resting-state functional magnetic resonance images were acquired, and the mean amplitude of low-frequency fluctuations (mALFF) were captured.Results: Nominal significant genotypic effect of rs10891819 in "ADHD-alone" subgroup was detected (P = 0.008) with TT genotype as protective. The results did not survive multiple testing correction. No direct genetic effect was found for performance on executive function tasks. In the imaging genetic study for the "ADHD-whole" sample, rs10891819 genotype was significantly associated with altered mALFF in the right superior frontal gyrus (rSFG, peak t = 3.85, corrected P < 0.05). Specifically, the mALFFs in T-allele carriers were consistently higher than GG carriers in ADHD and control groups. Endophenotypic correlation analyses indicated a significant negative correlation between "word interference time" in Stroop (shorter " word interference time" indexing better inhibitory function) and mALFF in the rSFG (r = -0.29, P = 0.006). Finally, mediation analysis confirmed significant indirect effects from "rs10891819 genotype (T-allele carriers)" via "mALFF (rSFG)" to "inhibition ("word interference time")" ( Sobelz = -2.47; B = -2.61, 95% confidence interval -0.48 to -4.72; P = 0.009).Conclusions: Our study offered preliminary evidence to implicate the roles of CADM1 in relation to prefrontal brain activities, inhibition function, and ADHD, indicating a potential "gene-brain-behavior" relationship of the CADM1 gene. Future studies with larger samples may specifically test these hypotheses generated by our exploratory findings.