Dataset Information

Analysis of protocadherin alpha gene enhancer polymorphism in bipolar disorder and schizophrenia.

ABSTRACT: Cadherins and protocadherins are cell adhesion proteins that play an important role in neuronal migration, differentiation and synaptogenesis, properties that make them targets to consider in schizophrenia (SZ) and bipolar disorder (BD) pathogenesis. Consequently, allelic variation occurring in protocadherin and cadherin encoding genes that map to regions of the genome targeted in SZ and BD linkage studies are particularly strong candidates to consider. One such set of candidate genes is the 5q31-linked PCDH family, which consists of more than 50 exons encoding three related, though distinct family members--alpha, beta, and gamma--which can generate thousands of different protocadherin proteins through alternative promoter usage and cis-alternative splicing. In this study, we focused on a SNP, rs31745, which is located in a putative PCDHalpha enhancer mapped by ChIP-chip using antibodies to covalently modified histone H3. A striking increase in homozygotes for the minor allele at this locus was detected in patients with BD. Molecular analysis revealed that the SNP causes allele-specific changes in binding to a brain protein. The findings suggest that the 5q31-linked PCDH locus should be more thoroughly considered as a disease-susceptibility locus in psychiatric disorders.

SUBMITTER: Pedrosa E

PROVIDER: S-EPMC2862380 | biostudies-literature | 2008 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Analysis of protocadherin alpha gene enhancer polymorphism in bipolar disorder and schizophrenia.

Pedrosa Erika E Stefanescu Radu R Margolis Benjamin B Petruolo Oriana O Lo Yungtai Y Nolan Karen K Novak Tomas T Stopkova Pavla P Lachman Herbert M HM

Schizophrenia research 20080527 1-3

Cadherins and protocadherins are cell adhesion proteins that play an important role in neuronal migration, differentiation and synaptogenesis, properties that make them targets to consider in schizophrenia (SZ) and bipolar disorder (BD) pathogenesis. Consequently, allelic variation occurring in protocadherin and cadherin encoding genes that map to regions of the genome targeted in SZ and BD linkage studies are particularly strong candidates to consider. One such set of candidate genes is the 5q3 ...[more]

PMID: 18508241

Similar Datasets

Project description:OBJECTIVE:Family and twin studies indicate substantial overlap of genetic influences on psychotic and mood disorders. Linkage and candidate gene studies have also suggested overlap across schizophrenia, bipolar disorder, and major depressive disorder. The purpose of this study was to apply genomewide association study (GWAS) analysis to address the specificity of genetic effects on these disorders. METHOD:The authors combined GWAS data from three large effectiveness studies of schizophrenia (CATIE, genotyped: N=741), bipolar disorder (STEP-BD, geno-typed: N=1,575), and major depressive disorder (STAR*D, genotyped: N=1,938) as well as from psychiatrically screened control subjects (NIMH-Genetics Repository: N=1,204). A two-stage analytic procedure involving an omnibus test of allele frequency differences among case and control groups was applied, followed by a model selection step to identify the best-fitting model of allelic effects across disorders. RESULTS:The strongest result was seen for a single nucleotide polymorphism near the adrenomedullin (ADM) gene (rs6484218), with the best-fitting model indicating that the effect was specific to bipolar II disorder. Findings also revealed evidence suggesting that several genes may have effects that transcend clinical diagnostic boundaries, including variants in NPAS3 that showed pleiotropic effects across schizophrenia, bipolar disorder, and major depressive disorder. CONCLUSIONS:This study provides the first genomewide significant evidence implicating variants near the ADM gene on chromosome 11p15 in psychopathology, with effects that appear to be specific to bipolar II disorder. Although genomewide significant evidence of cross-disorder effects was not detected, the results provide evidence that there are both pleiotropic and disorder-specific effects on major mental illness and illustrate an approach to dissecting the genetic basis of mood and psychotic disorders that can inform future large-scale cross-disorder GWAS analyses.

Project description:The transcription factor 4 (TCF4) gene encodes a helix-loop-helix transcription factor protein, which initiates neuronal differentiation and is primarily expressed during nervous system development. The aim of the present study is to investigate the association of the TCF4 rs9960767 polymorphism and bipolar disorder, which is highly heritable. DNA isolation was performed on 95 patients with bipolar disorder and 108 healthy control subjects to examine the TCF4 rs9960767 polymorphism. Genotypic and allelic frequencies were determined using the polymerase chain reaction-restriction fragment length polymorphism method designed in our laboratory. Statistical analysis was performed using ?2 test within the 95% confidence interval. Odds ratios were calculated and Hardy-Weinberg equilibrium (HWE) was verified for all control subjects and patients. The A allele frequency was 95.8% in the patients and 94.4% in the control subjects, and 4.2% in the patients and 5.6% in the control subjects for the C allele. The genotype frequencies of the TCF4 gene rs9960767 variant were as follows: AA, 91.6% and AC, 8.4% in patients with bipolar (CC genotype was not observed in cases); AA, 89.8%; AC, 9.3% and CC, 0.9% in the control subjects. No statistically significant difference was identified between the patients and control subjects (?2=0.937; P=0.626). In addition, gender specific analysis was performed, although no significant association was found according to the gender distrubition. All patients and control subjects were in HWE (P>0.05). Statistical analysis of the data indicates that the TCF4 gene rs9960767 polymorphism is not an independent risk factor for bipolar disorder in the overall population or in terms of gender; however, an increased population size would improve the statistical power. Furthermore, additional gene variants that are specifically involved in neuronal development may be analyzed for revealing the complex genetic architecture of bipolar disorder. An improved approach would be better to evaluate the TCF4 gene in a pathway specific manner due to its role as a transcription factor.

Dataset Information

Analysis of protocadherin alpha gene enhancer polymorphism in bipolar disorder and schizophrenia.

Publications

Analysis of protocadherin alpha gene enhancer polymorphism in bipolar disorder and schizophrenia.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets