TRPM2 variants and bipolar disorder risk: confirmation in a family-based association study.
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.
Xu
Chun
C
Laboratory of Cellular and Molecular Pathophysiology, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada.
Li
Peter P
PP
Cooke
Robert G
RG
Parikh
Sagar V
SV
Wang
KeSheng
K
Kennedy
James L
JL
Warsh
Jerry J
JJ
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
D050053:TRPM Cation Channels; C121934:TRPM2 protein, human