title: Cis-acting regulation of brain-specific ANK3 gene expression by a genetic variant associated with bipolar disorder.
abstract: Several genome-wide association studies for bipolar disorder (BD) have found a strong association of the Ankyrin 3 (ANK3) gene. This association spans numerous linked single-nucleotide polymorphisms (SNPs) in an ~250-kb genomic region overlapping ANK3. The associated region encompasses predicted regulatory elements as well as two of the six validated alternative first exons, which encode distinct protein domains at the N-terminus of the protein also known as Ankyrin-G. Using RNA ligase-mediated rapid amplification of cDNA ends 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 and coupling of specific 5' ends with 3' mRNA splicing events in postmortem 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 that may be relevant to BD pathophysiology.
authors: Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics, Research, Massachusetts General Hospital, Boston, MA, USA.
authors: E H
authors: EH
authors: Rueckert
authors: D
authors: D
authors: Barker
authors: D
authors: D
authors: Ruderfer
authors: S E
authors: SE
authors: Bergen
authors: C
authors: C
authors: O'Dushlaine
authors: C J
authors: CJ
authors: Luce
authors: S D
authors: SD
authors: Sheridan
authors: K M
authors: KM
authors: Theriault
authors: K
authors: K
authors: Chambert
authors: J
authors: J
authors: Moran
authors: S M
authors: SM
authors: Purcell
authors: J M
authors: JM
authors: Madison
authors: S J
authors: SJ
authors: Haggarty
authors: P
authors: P
authors: Sklar
mesh_terms: D000483:Alleles; D017487:Ankyrins / Q000235:genetics*; D001714:Bipolar Disorder / Q000235:genetics*; D001921:Brain / Q000378:metabolism*; D002478:Cells, Cultured; D005091:Exons; D005333:Fetus / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D009474:Neurons / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism
chemical_list: C490613:ANK3 protein, human; D017487:Ankyrins; D020033:Protein Isoforms