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

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.