This genome-wide association study and trans-ancestry meta-analysis explores the genetic basis of bipolar disorder in a Han Chinese population and assesses shared bipolar disorder genetic risk between Han Chinese and European populations. Importance The genetic basis of bipolar disorder (BD) in Han Chinese individuals is not fully understood. Objective To explore the genetic basis of BD in the Han Chinese population. Design, Setting, and Participants A genome-wide association study (GWAS), followed by independent replication, was conducted to identify BD risk loci in Han Chinese individuals. Individuals with BD were diagnosed based on DSM-IV criteria and had no history of schizophrenia, mental retardation, or substance dependence; individuals without any personal or family history of mental illnesses, including BD, were included as control participants. In total, discovery samples from 1822 patients and 4650 control participants passed quality control for the GWAS analysis. Replication analyses of samples from 958 patients and 2050 control participants were conducted. Summary statistics from the European Psychiatric Genomics Consortium 2 (PGC2) BD GWAS (20 352 cases and 31 358 controls) were used for the trans-ancestry genetic correlation analysis, polygenetic risk score analysis, and meta-analysis to compare BD genetic risk between Han Chinese and European individuals. The study was performed in February 2020. Main Outcomes and Measures Single-nucleotide variations with P < 5.00 x 10(-8) were considered to show genome-wide significance of statistical association. Results The Han Chinese discovery GWAS sample included 1822 cases (mean [SD] age, 35.43 [14.12] years; 838 [46%] male) and 4650 controls (mean [SD] age, 27.48 [5.97] years; 2465 [53%] male), and the replication sample included 958 cases (mean [SD] age, 37.82 [15.54] years; 412 [43%] male) and 2050 controls (mean [SD] age, 27.50 [6.00] years; 1189 [58%] male). A novel BD risk locus in Han Chinese individuals was found near the gene encoding transmembrane protein 108 (TMEM108, rs9863544; P = 2.49 x 10(-8); odds ratio [OR], 0.650; 95% CI, 0.559-0.756), which is required for dendritic spine development and glutamatergic transmission in the dentate gyrus. Trans-ancestry genetic correlation estimation (rho(ge) = 0.652, SE = 0.106; P = 7.30 x 10(-10)) and polygenetic risk score analyses (maximum liability-scaled Nagelkerke pseudo R-2 = 1.27%; P = 1.30 x 10(-19)) showed evidence of shared BD genetic risk between Han Chinese and European populations, and meta-analysis identified 2 new GWAS risk loci near VRK2 (rs41335055; P = 4.98 x 10(-9); OR, 0.849; 95% CI, 0.804-0.897) and RHEBL1 (rs7969091; P = 3.12 x 10(-8); OR, 0.932; 95% CI, 0.909-0.956). Conclusions and Relevance This GWAS study identified several loci and genes involved in the heritable risk of BD, providing insights into its genetic architecture and biological basis. Question What is the genetic architecture of bipolar disorder (BD) in the Han Chinese population? Findings In this genome-wide association study of 6472 individuals of Han Chinese ancestry (1822 cases and 4650 controls), several novel risk loci for BD were found, and trans-ancestry genetic correlation estimation and polygenic risk score analyses of Han Chinese and European individuals suggested a shared genetic risk of BD. Meaning Findings of this study highlighted novel genome-wide significant risk loci for BD that can provide insight into the genetic architecture of this disorder.