Association of Calcium Channel Gene Polymorphisms with Bipolar Disorder in a Taiwanese Sample

背景：近年來在躁鬱症(bipolar disorder, BPD)的全基因體掃描結果中，報告兩個分別位於電位控制式鈣離子通道(voltage-gated calcium channel, Cav)基因CACNA1C和CACNB2上的單一核苷酸變異和躁鬱症有相關。然而，在過去的遺傳相關性研究中，只有少數的Cav基因曾被探討與疾病間的相關。本研究試圖更廣泛地評估Cav基因家族中的數個基因上常見的遺傳變異是否和躁鬱症有相關，包括組成Cav通道的不同亞基(subunit)上的遺傳變異。 方法：本研究為一個病例－對照研究設計，共收集台灣地區280躁鬱症病人，以及200名健康對照。參考過去躁鬱症的遺傳相關性研究以及連鎖分析的結果，共挑選出七個Cav基因，包含CACNA1S, CACNA1C, CACNA1E, CACNB2, CACNG1, CACNG2 以及CACNG5基因。利用GoldenGate&reg; VeraCodeTM檢測技術，基因定型分析了13個單一核苷酸多型性。我們進行了單一基因座和多組基因座的相關性分析，並且利用Boolean operation based screening and testing方法，根據等位基因(allelic)和基因型(genotypic)兩種方式，探討各基因多型性間是否有交互作用存在。 結果：我們發現位於CACNA1C基因上的遺傳變異rs11013860和位於CACNG2基因上的遺傳變異rs2284018顯現出和躁鬱症最強的遺傳關聯性。在由四個遺傳變異(rs10848635, rs704326, rs11013860 和 rs2284018)組成的劑量效應分析中，我們發現當一個人帶有的危險基因型組數量增加的時候，罹患疾病的風險也隨之增加（趨勢檢定結果P < 0.02）。我們也發現組成Cav通道的不同亞基之間的遺傳變異可能有交互作用，其組合分別為CACNA1S-CACNA1E, CACNB2-CACNG2, CACNAB2-CACNG5, 和CACNA1C-CACNG5。 結論：從單一遺傳變異、多基因組到交互作用分析各方面的證據都顯示了Cav基因和躁鬱症之間的相關性。從我們的結果也可推測在亞洲族群中，位在Cav基因上的常見遺傳變異會增加得到躁鬱症的風險性。Objectives. Genetic variants in voltage-gated calcium channel (Cav) genes, CACNA1C and CACNB2, were reported to be associated with bipolar disorder (BPD) in recent genome-wide association studies. However, only a few Cav genes were identified in prior association studies. The current study aimed to first evaluate the associations between common variants in Cav gene family and BPD more extensively. We also performed analysis for multiple risk variants and to test interaction effects among different Cav genes that encode for subunits of calcium channel. Methods. A case-control association study for patients with BPD and healthy controls was conducted in Taiwan. We selected 7 Cav genes, including CACNA1S, CACNA1C, CACNA1E, CACNB2, CACNG1, CACNG2 and CACNG5, based on evidence in prior association studies and significant linkage regions for BPD. Genotyping for thirteen SNPs (single nucleotide polymorphisms) was performed using GoldenGate&reg; VeraCodeTM assays in 280 BPD patients and 200 controls. We conducted both single marker and multi-loci association analyses. Pair-wise interactions among SNPs using allelic and genotypic models were tested using the Boolean operation based screening and testing. Results. The strongest association was observed for rs11013860 in CACNA1C and rs2284018 in CACNG2 gene with BPD. A dose response analysis of four markers (rs10848635, rs704326, rs11013860 and rs2284018) revealed high accumulative risk for increasing numbers of risk genotypes an individual endorsed (trend test P < 0.02). Suggestive interactions were found between genes encoded for different subunits of calcium channel, including CACNA1S-CACNA1E, CACNB2-CACNG2, CACNAB2-CACNG5, and CACNA1C-CACNG5. Conclusions. Lines of evidence from single marker, multi-loci, and interactions analyses revealed the associations between calcium channel genes and bipolar disorder. Our results suggested the involvement of common genetic variants in calcium channel genes to confer the risk for developing bipolar disorder in an Asian population. Futher replication and basic research is needed to investigate the functional proerty of these genes to contribute on understanding etiological mechanism of bipolar illess