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

被引:0
|
作者
E H Rueckert
D Barker
D Ruderfer
S E Bergen
C O'Dushlaine
C J Luce
S D Sheridan
K M Theriault
K Chambert
J Moran
S M Purcell
J M Madison
S J Haggarty
P Sklar
机构
[1] Psychiatric and Neurodevelopmental Genetics Unit,Department of Psychiatry
[2] Center for Human Genetics,Department of Psychiatry
[3] Research,Department of Neurology
[4] Massachusetts General Hospital,undefined
[5] Harvard Medical School,undefined
[6] Stanley Center for Psychiatric Research,undefined
[7] Broad Institute of MIT and Harvard,undefined
[8] Analytic Translational Genetics Unit,undefined
[9] Massachusetts General Hospital,undefined
[10] Mount Sinai School of Medicine,undefined
[11] Harvard Medical School,undefined
[12] Center for Human Genetics Research,undefined
[13] Massachusetts General Hospital,undefined
来源
Molecular Psychiatry | 2013年 / 18卷
关键词
ANK3; Ankyrin-G (AnkG); axon initial segment; bipolar disorder; human neurons; stem cells;
D O I
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中图分类号
学科分类号
摘要
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.
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页码:922 / 929
页数:7
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