Yong Wu, Xiangyu Li, Yaoyao Sun, Chuyi Zhang, Ping Sun, Li Hui, Ying Zhao, Xiaoyang Feng, Baokun Wang, Jianzhong Yang, Nan Zhang, Jing Yuan, Hongyan Jiang, Yuqi Cheng, Simeng Ma, Qian Gong, Xuyuan Yin, Yongfeng Yang, Wenqiang Li, Luxian Lv, Dongsheng Zhou, Xingxing Li, Xiaogang Chen, Chen Zhang, Xueqin Song, Wenxin Tang, Zhongchun Liu, Yongyong Shi, Xiao Xiao, Weihua Yue, Zhiqiang Li, Ming Li
Although copy number variants (CNVs) represent well-established genetic contributors to schizophrenia (SCZ), their role in bipolar disorder (BD), especially within non-European ancestries, has been inadequately explored. We evaluated the genome-wide load of rare CNVs, encompassing deletions and duplications, in a Han Chinese sample of 3915 BD cases and 7820 ethnically matched controls. We observed a marked overrepresentation of rare deletions in BD patients relative to controls, with affected genes showing enrichment in neural signaling and dosage-dependent networks, indicating that haploinsufficiency in neurodevelopmental loci could underlie a central etiological pathway in BD. Among the 12 previously reported CNV loci from European cohorts, only deletions at 3q29 and 15q11.2 exhibited robust associations with BD susceptibility in Han Chinese individuals. Through genome-wide, gene-centric CNV association testing, we uncovered novel BD-linked loci, including deletions spanning GLIS2 and PAM16 at 16p13.3, GRID2IP at 7p22.1, and CFLAR at 2q33.1, alongside a duplication affecting ZNF878 and ZNF844 at 19p13.2. These disrupted genes are chiefly implicated in neuronal maturation, synaptic modulation, and mitochondrial dynamics. This work delivers the most thorough delineation of BD-associated CNVs in Han Chinese to date, underscoring the imperative for ancestry-inclusive research to comprehensively unravel psychiatric genomics and unveiling fresh mechanistic perspectives on BD etiology.