Peer Review Report For: Single Nucleotide Polymorphisms in ANK3 and Psychiatric Risk: A Meta-Analysis, Systematic Review, and Quantitative Trait Locus Insights [version 1; peer review: 1 approved with reservations]

Background Ankyrin 3 (Ankyrin G), encoded by the ANK3 gene, is a membrane-associated scaffold protein critical for neuronal signaling and highly enriched in axonal initial segments and nodes of Ranvier. ANK3 variants have been implicated in several neuropsychiatric disorders. Objectives To identify single nucleotide polymorphisms (SNPs) in ANK3 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 ANK3. 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 ANK3 SNPs and psychiatric disorders. In bipolar disorder, rs10994336 (OR = 1.28, P = 1.04×10 −4 ) 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 −12 ) and Asian populations (OR = 1.08, P = 4.68×10 −12 ), 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 ANK3 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 ANK3 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.