Association of the iPLA2β gene with bipolar disorder and assessment of its interaction with TRPM2 gene polymorphisms

Altered intracellular calcium homeostasis and oxidative stress are involved in the pathophysiology of bipolar disorder (BD)-I. To explore the genes contributing to these abnormalities, we examined the association with BD of the iPLA2 beta (PLA2G6), a signaling enzyme that mobilizes the arachidonic acid signaling cascade and activates oxidative stress, and assessed whether it interacts genetically with type 2 transient receptor potential channel gene (TRPM2), an oxidative stress-responsive calcium channel implicated both functionally and genetically in BD-I. Two tag single nucleotide polymorphisms rs4375 and rs3788533 in iPLA2 beta were genotyped in 446 White case-control individuals and 296 BD families using a 5'-nuclease TaqMan assay. The results were analyzed using chi(2)-test and transmission disequilibrium tests, and Haploview. In a secondary analysis, we tested gene-gene interactions between TRPM2 and iPLA2 beta on BD vulnerability by logistic regression using a case-only design in PLINK. iPLA2 beta-rs3788533 showed a borderline association with BD-I in patients with a history of psychosis in both case-control and family designs. Association with BD as a whole was observed in the family study (significant over transmissions of rs3788533-allele C, P=0.015, P-Bonferroni = 0.03, TDTPHASE). A borderline interaction was found between rs749909 within TRPM2 and rs4375 within iPLA2 beta (P-uncorrected = 0.009), on the basis of the case-only design analyzed with PLINK. A significant association of iPLA2 beta variants with BD-I and a trend gene-gene interaction between iPLA2 beta and TRPM2 provides additional support for the notion that genetic variation in these two functionally implicated candidates contributes toward the risk and pathophysiology of this illness. Psychiatr Genet 23: 86-89 (C) 2013 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. Psychiatric Genetics 2013, 23:86-89