Single nucleotide polymorphisms in ANK3 and psychiatric risk: a meta-analysis, systematic review, and quantitative trait locus insights

Abstract

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.

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Identifiers

ORCID for Yihua Wang: orcid.org/0000-0001-5561-0648

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