title: Association of the putative susceptibility gene, transient receptor potential protein melastatin type 2, with bipolar disorder.
abstract: Disturbed intracellular calcium (Ca(2+)) homeostasis has been implicated in bipolar disorder (BD). Reduced mRNA levels of the transient receptor potential Ca(2+) permeable channel melastatin type 2, TRPM2, in B lymphoblast cell lines (BLCL) from bipolar I disorder (BD-I) patients showing elevated basal intracellular Ca(2+) ([Ca(2+)](B)), an index of altered intracellular Ca(2+) homeostasis, along with its location within a putative BD susceptibility locus (21q22.3), implicates the involvement of this gene in the Ca(2+) abnormalities and the genetic diathesis to BD. We tested this hypothesis by examining the association of selected single nucleotide polymorphisms (SNPs) and their haplotypes, spanning the TRPM2 gene, with BD and BLCL [Ca(2+)](B), in a case control design. The 5' TaqMan SNP assay was used to detect selected SNPs. BLCL [Ca(2+)](B) was determined by ratiometric fluorometry. SNP rs1618355 in intron 18 was significantly associated with BD as a whole (P < 7.0 x 10(-5); odds ratio (OR) = 2.60), and when stratified into BD-I (P < 7.0 x 10(-5), OR = 2.48) and BD-II (P = 7.0 x 10(-5), OR = 2.88) subgroups. In addition, the alleles of the individual SNPs forming a seven marker at-risk haplotype were in excess in BD (12.0% in BD vs. 0.9% in controls; P = 2.3 x 10(-12)). A weak relationship was also detected between BLCL [Ca(2+)](B) and TRPM2 SNP rs1612472 in intron 19. These findings suggest genetic variants of the TRPM2 gene increase risk for BD and support the notion that TRPM2 may be involved in the pathophysiology of BD.
authors.affiliation: Laboratory of Cellular and Molecular Pathophysiology, Centre for Addiction and Mental Health, University of Toronto, 150 College Street, Toronto, Ontario, Canada M5T 1R8.
authors.forename: Chun
authors.initials: C
authors.lastname: Xu
authors.forename: Fabio
authors.initials: F
authors.lastname: Macciardi
authors.forename: Peter P
authors.initials: PP
authors.lastname: Li
authors.forename: Il-Sang
authors.initials: IS
authors.lastname: Yoon
authors.forename: Robert G
authors.initials: RG
authors.lastname: Cooke
authors.forename: Bronwen
authors.initials: B
authors.lastname: Hughes
authors.forename: Sagar V
authors.initials: SV
authors.lastname: Parikh
authors.forename: Roger S
authors.initials: RS
authors.lastname: McIntyre
authors.forename: James L
authors.initials: JL
authors.lastname: Kennedy
authors.forename: Jerry J
authors.initials: JJ
authors.lastname: Warsh
mesh_terms: D000328:Adult; D001483:Base Sequence; D001714:Bipolar Disorder / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050053:TRPM Cation Channels / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; D050053:TRPM Cation Channels; C121934:TRPM2 protein, human; D002118:Calcium