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.