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

Xu, Chuna,f; Warsh, Jerry J.a,b,c; Wang, Keng S.e; Mao, Chun X.d; Kennedy, James L.b

doi: 10.1097/YPG.0b013e32835d700d
Brief Reports

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 iPLA2β (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 iPLA2β were genotyped in 446 White case–control individuals and 296 BD families using a 5′-nuclease TaqMan assay. The results were analyzed using χ 2-test and transmission disequilibrium tests, and Haploview. In a secondary analysis, we tested gene–gene interactions between TRPM2 and iPLA2β on BD vulnerability by logistic regression using a case-only design in PLINK. iPLA2β-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 iPLA2β (P uncorrected=0.009), on the basis of the case-only design analyzed with PLINK. A significant association of iPLA2β variants with BD-I and a trend gene–gene interaction between iPLA2β 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.

aLaboratory of Cellular and Molecular Pathophysiology, Centre for Addiction and Mental Health

Departments of bPsychiatry

cPharmacology, University of Toronto

dUniversity of Toronto, Toronto, Ontario, Canada

eDepartment of Biostatistics and Epidemiology, College of Public Health, East Tennessee State University, Johnson City, Tennessee

fDepartment of Psychiatry and Neurology, Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine and The Center of Excellence in Neuroscience, El Paso, Texas, USA

Correspondence to Chun Xu, MD, MSc, PhD, Department of Psychiatry and Neurology, Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine and The Center of Excellence in Neuroscience, 5001 El Paso Drive, El Paso, Texas 79905, USA Tel: +1 915 783 5200; fax: +1 915 783 5223; e-mail: chun.xu@ttuhsc.edu

Received November 12, 2011

Accepted September 1, 2012

© 2013 Lippincott Williams & Wilkins, Inc.