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Association of the putative susceptibility gene, transient receptor potential protein melastatin type 2, with bipolar disorder
Author(s) -
Xu Chun,
Macciardi Fabio,
Li Peter P.,
Yoon IlSang,
Cooke Robert G.,
Hughes Bronwen,
Parikh Sagar V.,
McIntyre Roger S.,
Kennedy James L.,
Warsh Jerry J.
Publication year - 2005
Publication title -
american journal of medical genetics part b: neuropsychiatric genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.393
H-Index - 126
eISSN - 1552-485X
pISSN - 1552-4841
DOI - 10.1002/ajmg.b.30239
Subject(s) - single nucleotide polymorphism , trpm2 , haplotype , biology , snp , allele , genetics , genotype , microbiology and biotechnology , gene , transient receptor potential channel , receptor
Disturbed intracellular calcium (Ca 2+ ) homeostasis has been implicated in bipolar disorder (BD). Reduced mRNA levels of the t ransient r eceptor p otential Ca 2+ permeable channel m elastatin 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 × 10 −5 ; odds ratio (OR) = 2.60), and when stratified into BD‐I ( P < 7.0 × 10 −5 , OR = 2.48) and BD‐II ( P = 7.0 × 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 × 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. © 2005 Wiley‐Liss, Inc.