Promoter Activity-Based Case-Control Association Study on SLC6A4 Highlighting Hypermethylation and Altered Amygdala Volume in Male Patients With Schizophrenia
Promoter Activity-Based Case-Control Association Study on SLC6A4 Highlighting Hypermethylation and Altered Amygdala Volume in Male Patients With Schizophrenia
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DOI：
10.1093/schbul/sbaa075
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发表时间：
2020-11-01
影响因子：
6.6
通讯作者：
Iwamoto, Kazuya
中科院分区：
文献类型：
--
作者：
Ikegame, Tempei;Bundo, Miki;Iwamoto, Kazuya
5-羟色胺转运体(5-HTT)编码基因SLC6A4的DNA甲基化改变与早期生活逆境、情绪和焦虑障碍以及杏仁核反应性之间的关系已有报道。然而，很少有研究检查SLC6A4在精神分裂症(SZ)中的表观遗传学变化。我们研究了SLC6A4的CpG位点，其DNA甲基化水平已被报道在双相情感障碍中发生改变，使用了3个独立的SZ患者和年龄匹配的对照组。我们发现，在所有3个队列中，男性SZ患者SLC6A4中的一个CpG位点都存在显著的高甲基化。我们使用普通的绒猴表明，长期服用利培酮并不影响该CpG位点的DNA甲基化状态，而在体外，该CpG位点的DNA甲基化降低了SLC6A4的启动子活性。然后，我们对5-HTT连锁多态区域(5-HTTLPR)进行了基因分型，并利用脑成像数据研究了5-HTTLPR、DNA甲基化和杏仁核体积之间的关系。我们发现，携带低活性5-HTTLPR等位基因的患者表现出超甲基化，并且DNA甲基化水平与左侧杏仁核体积呈负相关。这些结果提示SLC6A4中CpG位点的高甲基化与SZ的病理生理有关，特别是在携带低活性5-HTTLPR等位基因的男性患者中。
Associations between altered DNA methylation of the serotonin transporter (5-HTT)-encoding gene SLC6A4 and early life adversity, mood and anxiety disorders, and amygdala reactivity have been reported. However, few studies have examined epigenetic alterations of SLC6A4 in schizophrenia (SZ). We examined CpG sites of SLC6A4, whose DNA methylation levels have been reported to be altered in bipolar disorder, using 3 independent cohorts of patients with SZ and age-matched controls. We found significant hypermethylation of a CpG site in SLC6A4 in male patients with SZ in all 3 cohorts. We showed that chronic administration of risperidone did not affect the DNA methylation status at this CpG site using common marmosets, and that in vitro DNA methylation at this CpG site diminished the promoter activity of SLC6A4. We then genotyped the 5-HTT-linked polymorphic region (5-HTTLPR) and investigated the relationship among 5-HTTLPR, DNA methylation, and amygdala volume using brain imaging data. We found that patients harboring low-activity 5-HTTLPR al-leles showed hypermethylation and they showed a negative correlation between DNA methylation levels and left amygdala volumes. These results suggest that hypermethylation of the CpG site in SLC6A4 is involved in the pathophysiology of SZ, especially in male patients harboring low-activity 5-HTTLPR alleles.