title: TRPM2 variants and bipolar disorder risk: confirmation in a family-based association study.
abstract: OBJECTIVE
  Recent case-control studies implicate the transient receptor potential melastatin 2 (TRPM2) channel in conferring risk for bipolar disorder (BD), though the risk variants differed. As confounding effects of population structure could not be unequivocally ruled out as the basis for the discordance, we tested the association of TRPM2 with BD in a family design, which is immune to population stratification, for those TRPM2 single nucleotide polymorphisms (SNPs) previously reported as associated with BD.
  
  
  METHODS
  The exon 11 SNP (rs1556314) and four informative intronic SNPs (rs1785437, rs1618355, rs933151, and rs749909) were genotyped in 300 BD families by TaqMan allelic discrimination and results were analyzed using chi(2) test, transmission disequilibrium test, and pedigree-based association. SNP rs1556314 was also genotyped in our case-control sample set comprised of 184 BD and 195 healthy Caucasian subjects.
  
  
  RESULTS
  The SNP rs1556314 in exon 11 was significantly associated with bipolar disorder type I (BD-I) (p = 0.011, p(permutation) = 0.015) in the case-control dataset and in the family design (p = 0.018, p(permutation) = 0.052, TDTPHASE). Interestingly, the C-T-A haplotype of SNPs rs1618355, rs933151, and rs749909 was significantly associated with early age at onset in BD-I families.
  
  
  CONCLUSIONS
  Significant association of TRPM2 genetic variants with BD in case-control and family datasets further supports a role for TRPM2 in the pathogenesis of this disorder. Overtransmission of the G allele of rs1556314 at exon 11 of TRPM2 in BD-I but not bipolar disorder type II (BD-II) further supports different genetic contributions to the pathogenesis of these bipolar phenotypes.
authors.affiliation: Laboratory of Cellular and Molecular Pathophysiology, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Chun
authors.initials: C
authors.lastname: Xu
authors.forename: Peter P
authors.initials: PP
authors.lastname: Li
authors.forename: Robert G
authors.initials: RG
authors.lastname: Cooke
authors.forename: Sagar V
authors.initials: SV
authors.lastname: Parikh
authors.forename: KeSheng
authors.initials: K
authors.lastname: Wang
authors.forename: James L
authors.initials: JL
authors.lastname: Kennedy
authors.forename: Jerry J
authors.initials: JJ
authors.lastname: Warsh
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D001714:Bipolar Disorder / Q000145:classification / Q000209:etiology / Q000235:genetics*; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D005091:Exons / Q000235:genetics; D005192:Family Health; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012306:Risk; D050053:TRPM Cation Channels / Q000235:genetics*; D055815:Young Adult
chemical_list: D050053:TRPM Cation Channels; C121934:TRPM2 protein, human