Nakatochi Masahiro, Kushima Itaru, Aleksic Branko, Kimura Hiroki, Kato Hidekazu, Inada Toshiya, Torii Youta, Takahashi Nagahide, Yamamoto Maeri, Iwamoto Kunihiro, Nawa Yoshihiro, Iritani Shuji, Iwata Nakao, Saito Takeo, Ninomiya Kohei, Okochi Tomo, Hashimoto Ryota, Yamamori Hidenaga, Yasuda Yuka, Fujimoto Michiko, Miura Kenichiro, Ohi Kazutaka, Shioiri Toshiki, Kitaichi Kiyoyuki, Itokawa Masanari, Arai Makoto, Miyashita Mitsuhiro, Toriumi Kazuya, Takahashi Tsutomu, Suzuki Michio, Kato Takahiro A, Kanba Shigenobu, Horikawa Hideki, Kasai Kiyoto, Ikegame Tempei, Jinde Seiichiro, Kato Tadafumi, Kakiuchi Chihiro, Yamagata Bun, Nio Shintaro, Kunii Yasuto, Yabe Hirooki, Okamura Yasunobu, Tadaka Shu, Fumihiko Ueno, Obara Taku, Yamamoto Yasuyuki, Arioka Yuko, Mori Daisuke, Ikeda Masashi, Ozaki Norio
Public Health Informatics Unit, Department of Integrated Health Science, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Psychiatry Clin Neurosci. 2025 Jan;79(1):12-20. doi: 10.1111/pcn.13752. Epub 2024 Oct 15.
Bipolar disorder (BD) is a common psychiatric disorder characterized by alterations between manic/hypomanic and depressive states. Rare pathogenic copy number variations (CNVs) that overlap with exons of synaptic genes have been associated with BD. However, no study has comprehensively explored CNVs in synaptic genes associated with BD. Here, we evaluated the relationship between BD and rare CNVs that overlap with synaptic genes, not limited to exons, in the Japanese population.
Using array comparative genome hybridization, we detected CNVs in 1839 patients with BD and 2760 controls. We used the Synaptic Gene Ontology database to identify rare CNVs that overlap with synaptic genes. Using gene-based analysis, we compared their frequencies between the BD and control groups. We also searched for synaptic gene sets related to BD. The significance level was set to a false discovery rate of 10%.
The RNF216 gene was significantly associated with BD (odds ratio, 4.51 [95% confidence interval, 1.66-14.89], false discovery rate < 10%). The BD-associated CNV that corresponded with RNF216 also partially overlapped with the minimal critical region of the 7p22.1 microduplication syndrome. The integral component of the postsynaptic membrane (Gene Ontology:0099055) was significantly associated with BD. The CNV overlapping with the intron region of GRM5 in this gene set showed a nominal significant association between cases and controls (P < 0.05).
We provide evidence that CNVs in RNF216 and postsynaptic membrane-related genes confer a risk of BD, contributing to a better understanding of the pathogenesis of BD.
双相情感障碍（BD）是一种常见的精神疾病，其特征为躁狂/轻躁狂与抑郁状态之间的交替。与突触基因外显子重叠的罕见致病性拷贝数变异（CNV）已与BD相关联。然而，尚无研究全面探索与BD相关的突触基因中的CNV。在此，我们评估了日本人群中BD与与突触基因重叠的罕见CNV之间的关系，不限于外显子。
使用阵列比较基因组杂交技术，我们在1839例BD患者和2760名对照中检测CNV。我们使用突触基因本体数据库来识别与突触基因重叠的罕见CNV。使用基于基因的分析，我们比较了BD组和对照组之间它们的频率。我们还搜索了与BD相关的突触基因集。显著性水平设定为错误发现率为10%。
RNF216基因与BD显著相关（优势比，4.51 [95%置信区间，1.66 - 14.89]，错误发现率<10%）。与RNF216对应的BD相关CNV也部分与7p22.1微重复综合征的最小关键区域重叠。突触后膜的整合成分（基因本体：0099055）与BD显著相关。该基因集中与GRM5内含子区域重叠的CNV在病例和对照之间显示出名义上的显著关联（P < 0.05）。
我们提供证据表明，RNF216和突触后膜相关基因中的CNV赋予了BD风险，有助于更好地理解BD的发病机制。
