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Re-sequencing of ankyrin 3 exon 48 and case-control association analysis of rare variants in bipolar disorder type I

Authors


Corresponding author:
Glenn A. Doyle, Ph.D.
Department of Psychiatry
Center for Neurobiology and Behavior
University of Pennsylvania Perelman School of Medicine
Translational Research Building, Room 2231-6
125 South 31st Street
Philadelphia, PA 19104
USA
Fax: 215-573-2041
E-mail: gadoyle@mail.med.upenn.edu

Abstract

Doyle GA, Lai AT, Chou AD, Wang M-J, Gai X, Rappaport EF, Berrettini WH. Re-sequencing of ankyrin 3 exon 48 and case-control association analysis of rare variants in bipolar disorder type I. Bipolar Disord 2012: 14: 809–821. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S.

Objectives:  Genome-wide association studies (GWAS) recently identified ankyrin 3 (ANK3) as a candidate gene for bipolar disorder type I (BPD-I). Because the GWAS suggested multiple common haplotypes associated with BPD-I (with odds ratio ∼1.3), we hypothesized that rare variants within these common haplotypes might increase risk for BPD-I.

Methods:  We undertook a project in which the serine-rich domain–tail domain (SRD-TD)-encoding exon of ANK3 was amplified from genomic DNA (gDNA) of 384 BPD-I patients and re-sequenced by next generation sequencing (NGS; SOLiD™).

Results:  We confirmed 18 novel mis-sense rare variants and one novel insertion/deletion variant within the SRD-TD exon, many of which change amino acid residues with extremely high evolutionary conservation. We genotyped most of these mis-sense variants in ≥ 1000 BPD-I and ≥ 1000 control individuals. We found no statistically significant association of any of the rare variants detected with BPD-I.

Conclusions:  Thus, we conclude that rare variants within the re-sequenced structural domains of ANK3 exon 48 do not contribute to BPD-I.

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