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. CONCLUSION 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.

[1]  John N. Hutchinson,et al.  Widespread Monoallelic Expression on Human Autosomes , 2007, Science.

[2]  Xin Xu,et al.  Implementing a unified approach to family‐based tests of association , 2000, Genetic epidemiology.

[3]  M. Leboyer,et al.  Age at onset in bipolar affective disorders: a review. , 2005, Bipolar disorders.

[4]  E. Mundo,et al.  Suicide risk in bipolar patients: the role of co-morbid substance use disorders. , 2003, Bipolar disorders.

[5]  P. Donnelly,et al.  The effects of human population structure on large genetic association studies , 2004, Nature Genetics.

[6]  R. McIntyre,et al.  Association of the putative susceptibility gene, transient receptor potential protein melastatin type 2, with bipolar disorder , 2006, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[7]  Christoph Lange,et al.  PBAT: tools for family-based association studies. , 2004, American journal of human genetics.

[8]  Christoph Lange,et al.  Family‐based association tests for survival and times‐to‐onset analysis , 2004, Statistics in medicine.

[9]  S. Dobrin,et al.  Candidate gene analysis of 21q22: Support for S100B as a susceptibility gene for bipolar affective disorder with psychosis , 2007, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[10]  Kenneth K Kidd,et al.  Significant variation in haplotype block structure but conservation in tagSNP patterns among global populations , 2007, European Journal of Human Genetics.

[11]  J. Ioannidis,et al.  Replication validity of genetic association studies , 2001, Nature Genetics.

[12]  Julian C. Knight,et al.  Regulatory polymorphisms underlying complex disease traits , 2005, Journal of Molecular Medicine.

[13]  H. Ujike,et al.  The GABA type A receptor α5 subunit gene is associated with bipolar I disorder , 2005, Neuroscience Letters.

[14]  J. Eisfeld,et al.  Activation of the Cation Channel Long Transient Receptor Potential Channel 2 (LTRPC2) by Hydrogen Peroxide , 2002, The Journal of Biological Chemistry.

[15]  M. Alda,et al.  The phenotypes of bipolar disorder: relevance for genetic investigations , 2005, Molecular Psychiatry.

[16]  Eden R Martin,et al.  No gene is an island: the flip-flop phenomenon. , 2007, American journal of human genetics.

[17]  J. Nurnberger,et al.  Molecular genetics of bipolar disorder , 2005, Genes, brain, and behavior.

[18]  J. Nurnberger,et al.  A rapid non-enzymatic method for the preparation of HMW DNA from blood for RFLP studies. , 1991, Nucleic acids research.

[19]  A. Perraud,et al.  TRPM2 Ca2+ permeable cation channels: from gene to biological function. , 2003, Cell calcium.

[20]  N. Craddock,et al.  Genetics of affective (mood) disorders , 2006, European Journal of Human Genetics.

[21]  B. Frey,et al.  Increased oxidative stress after repeated amphetamine exposure: possible relevance as a model of mania. , 2006, Bipolar disorders.

[22]  D. Botstein,et al.  Genome-wide scan of bipolar disorder in 65 pedigrees: supportive evidence for linkage at 8q24, 18q22, 4q32, 2p12, and 13q12 , 2003, Molecular Psychiatry.

[23]  M. Owen,et al.  Phenotypic variation between parent-offspring trios and non-trios in genetic studies of schizophrenia. , 2006, Journal of psychiatric research.

[24]  Asta Försti,et al.  Opinion: The balance between heritable and environmental aetiology of human disease , 2006, Nature Reviews Genetics.

[25]  N. Wray,et al.  Association analysis of the chromosome 4p-located G protein-coupled receptor 78 (GPR78) gene in bipolar affective disorder and schizophrenia , 2006, Molecular Psychiatry.

[26]  P. Donnelly,et al.  Replicating genotype–phenotype associations , 2007, Nature.

[27]  B. A. Miller,et al.  The Role of TRP Channels in Oxidative Stress-induced Cell Death , 2006, The Journal of Membrane Biology.

[28]  M. Daly,et al.  Genome-wide association studies for common diseases and complex traits , 2005, Nature Reviews Genetics.

[29]  J. Potash,et al.  Searching high and low: a review of the genetics of bipolar disorder. , 2000, Bipolar disorders.

[30]  A. McQuillin,et al.  Fine mapping of a susceptibility locus for bipolar and genetically related unipolar affective disorders, to a region containing the C21ORF29 and TRPM2 genes on chromosome 21q22.3 , 2006, Molecular Psychiatry.

[31]  W. Drevets,et al.  Toward Constructing an Endophenotype Strategy for Bipolar Disorders , 2006, Biological Psychiatry.

[32]  J. Kennedy,et al.  Altered TRPC7 gene expression in bipolar-I disorder , 2001, Biological Psychiatry.

[33]  Simon C. Potter,et al.  Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls , 2007, Nature.

[34]  S. Cichon,et al.  Caught in the trio trap? Potential selection bias inherent to association studies using parent-offspring trios. , 2001, American journal of medical genetics.

[35]  R. Kerwin,et al.  Evidence that the N-methyl-D-aspartate subunit 1 receptor gene (GRIN1) confers susceptibility to bipolar disorder , 2003, Molecular Psychiatry.

[36]  G. MacQueen,et al.  Bipolar II disorder: symptoms, course, and response to treatment. , 2001, Psychiatric services.

[37]  P. Zandi,et al.  Differential Expression of Disrupted-in-Schizophrenia (DISC1) in Bipolar Disorder , 2006, Biological Psychiatry.

[38]  N. Kato,et al.  Aberrant DNA methylation associated with bipolar disorder identified from discordant monozygotic twins , 2008, Molecular Psychiatry.

[39]  J. Warsh,et al.  Impaired Endoplasmic Reticulum Stress Response in B-Lymphoblasts From Patients With Bipolar-I Disorder , 2007, Biological Psychiatry.

[40]  J. Warsh,et al.  Role of intracellular calcium signaling in the pathophysiology and pharmacotherapy of bipolar disorder: current status , 2004, Clinical Neuroscience Research.

[41]  D. Clayton,et al.  A generalization of the transmission/disequilibrium test for uncertain-haplotype transmission. , 1999, American journal of human genetics.

[42]  D. Hunter.  Gene–environment interactions in human diseases , 2005, Nature Reviews Genetics.

[43]  Y. Okada.  Ion Channel Roles in Cell Death Induction , 2006, The Journal of Membrane Biology.

[44]  F. McMahon,et al.  Loci on chromosomes 6q and 6p interact to increase susceptibility to bipolar affective disorder in the national institute of mental health genetics initiative pedigrees , 2004, Biological Psychiatry.

[45]  M. Rietschel,et al.  What is familial about familial bipolar disorder? Resemblance among relatives across a broad spectrum of phenotypic characteristics. , 2006, Archives of general psychiatry.

[46]  M. Rietschel,et al.  Age at onset in bipolar I affective disorder: further evidence for three subgroups. , 2003, The American journal of psychiatry.