Abstract
PURPOSE: This pioneering study aimed to explore the associations between the A-kinase anchoring protein 11 (AKAP11) gene and bipolar disorder (BD) in a Chinese population. We sought to replicate findings from European populations regarding ultra-rare protein-truncating variants (PTVs) within exon 8 of AKAP11 and identify any novel rare mutations linked to Chinese BD patients. METHODS: We conducted a case-control association study, including a cohort of 284 Chinese BD patients, with the control group comprising 10,588 individuals from the China Metabolic Analytics Project (ChinaMAP) database. Polymerase chain reaction (PCR) amplification and Sanger sequencing were performed to analyze exon 8 of the AKAP11 gene. Statistical analysis involved chi-square tests on VassarStats to assess allele frequency differences between BD patients and the control group, along with power analysis using PASS (version 21.0.3). RESULTS: In 284 Chinese BD patients, within exon 8 of the AKAP11 gene we did not find any ultra-rare PTVs previously identified in European BD patients. However, five additional rare variants were discovered, including three missense variants and two synonymous variants. Notably, rs2236364 showed concordant deleterious predictions across four computational tools, warranting prioritized investigation. Statistical analysis revealed no significant difference in allele frequencies between groups (P= 0.240), although a slightly higher proportion of rare variants was observed in cases versus controls. Additionally, three variants were not documented in the Bipolar Exomes Browser (BipEx) database, the frequencies of the other two were mildly lower in cases than controls, contrary to the trend observed in the Chinese population. The observed difference may be due to population genetic-environmental interaction. CONCLUSION: In this pioneering Chinese population study of BD-AKAP11, we did not replicate the association of ultra-rare PTVs but identified five additional rare variants. Population-specific distribution patterns-exemplified by rs2236364 with computationally deleterious predictions-warrant validation in expanded cohorts to elucidate trans-ethnic risk mechanisms.