F35. ASSOCIATION STUDY BETWEEN CACNA1C AND ANK3 GENES IN THE ETIOLOGY OF BIPOLAR DISORDER IN MEXICAN PATIENTS

• Published in: European neuropsychopharmacology Vol. 75; p. S239
• Main Authors: Sosa, Ana Paula Nava, Hernandez, Sandra, Sanabrais-Jiménez, Marco Antonio, Ramirez, Carlo Esteban Sotelo, Cedillo, Ingrid Pamela Morales, Camarena, Beatriz
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01-10-2023
• ISSN: 0924-977X; 1873-7862
• DOI: 10.1016/j.euroneuro.2023.08.423

Bipolar disorder (BD) is a mental illness characterized by extreme mood changes, energy, activity levels, and behavior. Genetic epidemiology studies suggested that genetic factors are involved in the etiology of BD. Voltage dependent L type calcium channel, alpha 1C subunit (CACNA1C) play an important role in dendritic development, neuronal survival, synaptic plasticity, memory formation, learning, and behavior. Ankyrin 3 (ANK3) encodes the ankyrin G scaffold protein functioning in various biological processes. The most recognized function of ankyrin G in the brain is the formation and maintenance of the axon initial segment of neurons. Both genes have reported association with BD in GWAS and candidate gene studies. The aim of the study was explored the association of ANK3 and CACNA1C in the development of BD.
The study included 246 Mexican patients with BD according to DSM-IVRT and DSM-5 and 488 healthy controls. Genotyping was performed by allelic discrimination using TaqMan probes by real-time PCR for polymorphisms of CACNA1C (rs1006737, rs2370413) and ANK3 (rs9804190, rs1938526) genes. Statistical analysis of genotypes and alleles were performed with chi-square test. Linkage disequilibrium (LD) was obtained using the Haploview program and haplotype analysis using the Thesias program. Gene-gene interaction analysis (GXG) was carried out using the MDR program.
In the analysis of genotype and allele frequencies, we found association between rs1938526 of ANK3 and BD (x²= 13.1, 2gL, p= 0.001; x²=6.7, 1gL, p= 0.009, respectively) compared with the control subjects. However, the other polymorphisms evaluated of the CACNA1C and ANK3 gene did not show an association with the etiology of BD after Bonferroni correction (p > 0.0125). Furthermore, the CG and TA haplotypes of the ANK3 gene showed a lower frequency in patients compared to controls (p=0.001; p=0.03, respectively). Finally, an epistatic effect was found between CACNA1C and ANK3 genes, increasing 2.19 times the risk of developing BD (OR: 2.19 (95% CI 1.59-3.01); p= < 0.001).
BD is a heterogenous and complex disorder with a combination of environmental, psychological and genetic factors. Identify those genetic factors is important due to the BD heritability is between 79-93%. The present study shows an association between CACNA1C and ANK3 genes and BD etiology. Previous studies performed in European population have shown a genetic association between CACNA1C and ANK3 genes, however contradictory results have been found in studies performed in different populations. To our knowledge, this is the first GXG interaction study that involves CACNA1C and ANK3 genes in BD Mexican population. In conclusion, our findings suggests that ANK3 and CACNA1C increase the risk to develop BD. Nevertheless, these findings should be analyzed in a larger sample of BD patients including other neurobiological markers.