Abstract
Genetic analyses for bipolar disorder (BD) have achieved prominent success in Europeans in recent years, whereas its genetic basis in other populations remains relatively less understood. We herein report that the leading risk locus for BD in European genome-wide association studies (GWAS), the single-nucleotide polymorphism (SNP) rs9834970 near TRANK1 at 3p22 region, is also genome-wide significantly associated with BD in a meta-analysis of four independent East Asian samples including 5748 cases and 65,361 controls (p = 2.27 × 10−8, odds ratio = 1.136). Expression quantitative trait loci (eQTL) analyses and summary data-based Mendelian randomization (SMR) analyses in multiple human brain samples suggest that lower TRANK1 mRNA expression is a principal BD risk factor explaining its genetic risk signals at 3p22. We also identified another SNP rs4789 in the 3′ untranslated region (3′UTR) of TRANK1 showing stronger eQTL associations as well as genome-wide significant association with BD. Despite the relatively unclear neuronal function of TRANK1, our mRNA expression analyses in the human brains and in rat primary cortical neurons reveal that genes highly correlated with TRANK1 are significantly enriched in the biological processes related to dendritic spine, synaptic plasticity, axon guidance and circadian entrainment, and are also more likely to exhibit strong associations in psychiatric GWAS (e.g., the CACNA1C gene). Overall, our results support that TRANK1 is a potential BD risk gene. Further studies elucidating its roles in this illness are needed.
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Acknowledgements
We acknowledge with appreciation all the individuals with bipolar disorders and healthy controls whose contributions made this work possible. We are deeply grateful to all the participants working on this project. The authors wish to acknowledge Dr. Bernard Ng (Departments of Statistics and Medical Genetics, University of British Columbia, Vancouver, BC, Canada), Dr. Sara Mostafavi (Departments of Statistics and Medical Genetics, University of British Columbia, Vancouver, BC, Canada), and Dr. Philip L De Jager (Broad Institute, Cambridge, MA, USA) for providing the individual-level TRANK1 expression and genotypes in the Brain xQTL dataset.
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H.C., L.L., and M.L. conceived the study and interpreted the results. W.L., X.C., M.S., H.-J.L., L.Z., W.L., and L.W. performed the DNA extraction, SNP genotyping, statistical analysis, and the primary experiments. H.-J.L. and C.-Y.Z. performed the RNA-seq and pathway analysis. W.L., M.S., Y.Y., L.Z., M.S., Y.Z., C.Z., D.-S.Z., X.L., L.H., Q.-F.J., N.Q., B.-L.Z., S.-F.Z., J.C., B.X., Y.L., X.S., W.F., W.T., W.T., J.T., X.C., Y.F., and L.L. carried out subject recruitment and phenotype analysis. W.Y. and D.Z. contributed to design of sample analysis. X.X., H.C., L.L., and M.L. drafted the manuscript, and all authors contributed to the final version of the paper.
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Li, W., Cai, X., Li, HJ. et al. Independent replications and integrative analyses confirm TRANK1 as a susceptibility gene for bipolar disorder. Neuropsychopharmacol. 46, 1103–1112 (2021). https://doi.org/10.1038/s41386-020-00788-4
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DOI: https://doi.org/10.1038/s41386-020-00788-4
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