Single Nucleotide Polymorphisms in ANK3 and Psychiatric Risk: A Meta-Analysis, Systematic Review, and Quantitative Trait Locus Insights

<ns3:p>Background Ankyrin 3 (Ankyrin G), encoded by the <ns3:italic>ANK3</ns3:italic> gene, is a membrane-associated scaffold protein critical for neuronal signaling and highly enriched in axonal initial segments and nodes of Ranvier. <ns3:italic>ANK3</ns3:italic> variants have been implicated in several neuropsychiatric disorders. Objectives To identify single nucleotide polymorphisms (SNPs) in <ns3:italic>ANK3</ns3:italic> associated with psychiatric disorders, assess population-specific significance, determine variant locations, and explore regulatory effects through quantitative trait locus (QTL) analysis. Methods A meta-analysis and systematic literature review were conducted to identify disease-associated SNPs in <ns3:italic>ANK3.</ns3:italic> QTL analyses were performed using datasets from the eQTL Catalogue and GTEx v10 to evaluate regulatory effects in brain tissues. Results Meta-analysis identified significant associations between <ns3:italic>ANK3</ns3:italic> SNPs and psychiatric disorders. In bipolar disorder, rs10994336 (OR = 1.28, P = 1.04×10<ns3:sup>−4</ns3:sup>) was significant in European+North American populations; rs9804190 was protective in Europeans (OR = 0.88, P = 0.020); and rs1938526 was significant in both European+North American (OR = 1.32, P = 7.26×10<ns3:sup>−12</ns3:sup>) and Asian populations (OR = 1.08, P = 4.68×10<ns3:sup>−12</ns3:sup>), with an overall effect (OR = 1.17, P = 0.003). In schizophrenia, rs10761482 showed opposite effects: protective in Chinese (OR = 0.74, P = 0.002) and risk-associated in Iranian cohorts (OR = 1.57, P = 0.025). rs10994359 was protective in major depressive disorder in Asians (OR = 0.69, P = 0.016), and three SNPs reduced PTSD risk (OR = 0.48, P = 0.045). All significant variants were intronic. QTL analyses showed rs10761482 increased <ns3:italic>ANK3</ns3:italic> expression in neocortex (P = 0.001) and neurons (P = 0.038); three PTSD SNPs showed robust cerebellar splicing effects (FDR = 0.010); and apaQTLs indicated modest 3′-UTR effects in putamen. Conclusion Multiple intronic <ns3:italic>ANK3</ns3:italic> SNPs are significantly associated with psychiatric disorders and display tissue-specific regulatory effects. Integrating QTL data provides insights into their potential functional roles in neuropsychiatric pathogenesis.</ns3:p>