Department of Psychiatry, Center for Neurobiology and Behavior, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
Bipolar Disord. 2012 Dec;14(8):809-21. doi: 10.1111/bdi.12002. Epub 2012 Sep 11.
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.
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™).
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.
Thus, we conclude that rare variants within the re-sequenced structural domains of ANK3 exon 48 do not contribute to BPD-I.
全基因组关联研究（GWAS）最近将锚蛋白 3（ANK3）鉴定为 I 型双相情感障碍（BPD-I）的候选基因。由于 GWAS 提示与 BPD-I 相关的多个常见单倍型（优势比~1.3），我们假设这些常见单倍型内的罕见变异可能会增加 BPD-I 的风险。
我们开展了一项研究，从 384 名 BPD-I 患者的基因组 DNA（gDNA）中扩增 ANK3 的丝氨酸丰富结构域-尾部结构域（SRD-TD）编码外显子，并通过下一代测序（NGS；SOLiD™）进行重测序。
我们在 SRD-TD 外显子中证实了 18 个新的错义稀有变异和一个新的插入/缺失变异，其中许多变异改变了具有极高进化保守性的氨基酸残基。我们对这些错义变异中的大多数进行了基因分型，在≥1000 名 BPD-I 和≥1000 名对照个体中进行了基因分型。我们没有发现任何检测到的稀有变异与 BPD-I 之间存在统计学显著关联。
因此，我们得出结论，ANK3 外显子 48 中重测序结构域内的稀有变异不会导致 BPD-I。
