Cis-acting regulation of brain-specific ANK3 gene expression by a genetic variant associated with bipolar disorder

Abstract

Several genome-wide association studies (GWAS) for bipolar disorder (BD) have found a strong association of the Ankyrin3 (ANK3) gene. This association spans numerous linked single nucleotide polymorphisms (SNPs) in a ~250 kb genomic region overlapping ANK3. The associated region encompasses predicted regulatory elements as well as two of six validated alternative first exons, which encode distinct protein domains at the N-terminus of the protein also known as ankyrin-G (AnkG). Using RNA Ligase-Mediated Rapid Amplification of cDNA Ends (RLM-RACE) to identify novel transcripts in conjunction with a highly sensitive, exon-specific multiplexed mRNA expression assay, we detected differential regulation of distinct ANK3 transcription start sites (TSSs) and coupling of specific 5’ ends with 3’ mRNA splicing events in post-mortem human brain and human stem cell-derived neural progenitors and neurons. Furthermore, allelic variation at the BD–associated SNP rs1938526 correlated with a significant difference in cerebellar expression of a brain-specific ANK3 transcript. These findings suggest a brain-specific cis-regulatory transcriptional effect of ANK3 may be relevant to BD pathophysiology.

Association of a risk allele of ANK3 with cognitive performance and cortical thickness in patients with first-episode psychosis

“…Since the 2 SNPs are in strong linkage disequilibrium (d' = 0.95), results are only presented for rs1938526 given evidence of an effect of this SNP on gene expression. 19 Analyses on the effects of rs10994336 on neurocognition (not shown) yielded similar but slightly less significant results. Table 2 and Table S1 in the Appendix, available at cma.ca/jpn, indicate the clinical and demographic characteristics of participants included in both the cognitive and imaging portions of the study.…”

“…16,18 The risk-associated ANK3 SNPs are intronic, and rs1938526 and other SNPs have been associated with reduced gene expression. 16,19 Several studies have examined the role of these genetic variants on neurocognition. A study on BD found significant association between rs10994336 and sustained attention, but no effect on general intelligence, memory or executive functioning.…”

Genetic disruption of ankyrin-G in adult mouse forebrain causes cortical synapse alteration and behavior reminiscent of bipolar disorder

“…Studies were not powered to detect sex differences or sex × gene interactions. The human variation in ANK3 may also change splicing or regional brain expression in ways not modeled in the current study (7,11,13,14,53).…”

“…The 190-kDa isoform is present at dendritic spines (11,12). Many of the risk alleles for ANK3 are in the five-prime upstream region, suggestive of changes of expression (13,14). Ankyrin-G protein expression was reduced in pyramidal AISs in superficial layers of schizophrenia cortex (15).…”

An Ankyrin-G N-terminal Gate and Protein Kinase CK2 Dually Regulate Binding of Voltage-gated Sodium and KCNQ2/3 Potassium Channels

“…ANK3 Alternative N Termini Differentially Regulate KCNQ2/3 and Na v Channel Association with AnkG-ANK3 has at least three alternative promoters and corresponding first exons encoding non-ankyrin N termini variants (namely exon1a, exon1e, and exon1b, encoding NT1-3, respectively; Fig. 9, A and B) (6,42,45,46). These promoters and alternative N termini exhibit tissue-and cell type-specific expression.…”