Exploring the associations between genetic variants in genes encoding for subunits of calcium channel and subtypes of bipolar disorder.

BACKGROUND: Associations of two voltage-gated calcium channel (Cav) genes, CACNA1C and CACNB2, were identified for bipolar disorder (BP) in different ethnic groups in recent genome-wide association studies. The current study aimed to evaluate the associations of several Cav genes and subtypes of BP in genetically more homogeneous Taiwanese samples. Additionally, we tested interaction effects among genes that encode for α1, ß and γ-subunits of calcium channel. METHODS: 8 Cav genes were selected based on evidence in prior association studies and significant linkage regions for BP. 280 BP patients and 200 controls were recruited. Multifactor dimensionality reduction was performed for interaction testing in these discovery samples. Replication was conducted for two markers using additional 495 Taiwanese cases and 1341 controls. RESULTS: Weak associations for CACNA1C (rs10848635), CACNA1E (rs10848635), CACNB2 (rs11013860), and CACNG2 (rs2284018) genes were observed. Joint analysis of four markers revealed higher accumulative risk with increasing numbers of risk genotypes an individual endorsed for BP-I (Ptrend=0.006) and BP-II (Ptrend=0.017) disorders. Combined analysis with independent replication samples further supported the association of rs11013860 in CACNB2 with BP subtype I (P=1×10(-6)). Suggestive interactions were found between genes encoded for different subunits of calcium channel (α1, ß, and γ). LIMITATIONS: Moderate sample size and incomplete markers coverage for the chosen Cav genes. CONCLUSIONS: Our results support the involvement of different calcium channel genes in bipolar illness, in particular the beta-subunit in the Asian population. Further investigation of functional property of these genes can contribute on understanding the etiological mechanisms of bipolar illness.