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No evidence for association between 19 cholinergic genes and bipolar disorder.

ABSTRACT: Cholinergic dysfunction has been proposed for the pathogenesis of bipolar disorder (BD), and we have therefore performed a systematic association study of cholinergic system genes in BD (including schizoaffective disorder bipolar type). We genotyped 93 single nucleotide polymorphisms (SNPs) in 19 genes (CHAT, CHRM1-5, CHRNA1-7, CHRNA9, CHRNA10, and CHRNB1-4) in two series of samples: the National Institute of Mental Health (NIMH) Genetics Initiative pedigrees with 474 samples from 152 families, and the Clinical Neurogenetics (CNG) pedigrees with 83 samples from 22 multiplex families. Sib-transmission/disequilibrium test (sib_TDT) analysis showed nominally significant transmission bias for four SNPs (CHRNA2: rs7017417, P = 0.024; CHRNA5: rs514743, P = 0.031; CHRNB1: rs2302762, P = 0.049; CHRNB4: rs1948, P = 0.031). Haploview analyses showed nominally significant transmission bias of several haplotypes in CHRNA2, CHRNA7, CHRNB1, and CHRNB4, respectively. However, none of these associations reached gene-wide significance after correction by permutation. Alcohol dependence (including alcohol abuse) was not a significant covariate in the present genetic association analysis. Thus, it is unlikely that these 19 cholinergic genes play a major role in the pre-disposition to BD in these pedigrees.

SUBMITTER: Shi J

PROVIDER: S-EPMC2576477 | biostudies-literature | 2007 Sep

REPOSITORIES: biostudies-literature

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No evidence for association between 19 cholinergic genes and bipolar disorder.

Shi Jiajun J Hattori Eiji E Zou Hongwei H Badner Judith A JA Christian Susan L SL Gershon Elliot S ES Liu Chunyu C

American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 20070901 6

Cholinergic dysfunction has been proposed for the pathogenesis of bipolar disorder (BD), and we have therefore performed a systematic association study of cholinergic system genes in BD (including schizoaffective disorder bipolar type). We genotyped 93 single nucleotide polymorphisms (SNPs) in 19 genes (CHAT, CHRM1-5, CHRNA1-7, CHRNA9, CHRNA10, and CHRNB1-4) in two series of samples: the National Institute of Mental Health (NIMH) Genetics Initiative pedigrees with 474 samples from 152 families, ...[more]

PMID: 17373692

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Project description:BackgroundBipolar disorder, particularly in children, is characterized by rapid cycling and switching, making circadian clock genes plausible molecular underpinnings for bipolar disorder. We previously reported work establishing mice lacking the clock gene D-box binding protein (DBP) as a stress-reactive genetic animal model of bipolar disorder. Microarray studies revealed that expression of two closely related clock genes, RAR-related orphan receptors alpha (RORA) and beta (RORB), was altered in these mice. These retinoid-related receptors are involved in a number of pathways including neurogenesis, stress response, and modulation of circadian rhythms. Here we report association studies between bipolar disorder and single-nucleotide polymorphisms (SNPs) in RORA and RORB.MethodsWe genotyped 355 RORA and RORB SNPs in a pediatric cohort consisting of a family-based sample of 153 trios and an independent, non-overlapping case-control sample of 152 cases and 140 controls. Bipolar disorder in children and adolescents is characterized by increased stress reactivity and frequent episodes of shorter duration; thus our cohort provides a potentially enriched sample for identifying genes involved in cycling and switching.ResultsWe report that four intronic RORB SNPs showed positive associations with the pediatric bipolar phenotype that survived Bonferroni correction for multiple comparisons in the case-control sample. Three RORB haplotype blocks implicating an additional 11 SNPs were also associated with the disease in the case-control sample. However, these significant associations were not replicated in the sample of trios. There was no evidence for association between pediatric bipolar disorder and any RORA SNPs or haplotype blocks after multiple-test correction. In addition, we found no strong evidence for association between the age-at-onset of bipolar disorder with any RORA or RORB SNPs.ConclusionOur findings suggest that clock genes in general and RORB in particular may be important candidates for further investigation in the search for the molecular basis of bipolar disorder.

Project description:ContextThe Wnt signaling pathways promote cell growth and are best known for their role in embryogenesis and cancer. Several lines of evidence suggest that these pathways might also be involved in bipolar disorder.ObjectiveTo test for an association between candidate genes in the Wnt signaling pathways and disease susceptibility in a family-based bipolar disorder study.DesignTwo hundred twenty-seven tagging single- nucleotide polymorphisms (SNPs) from 34 genes were successfully genotyped. Initial results led us to focus on the gene PPARD, in which we genotyped an additional 13 SNPs for follow-up.SettingNine academic medical centers in the United States.ParticipantsFive hundred fifty-four offspring with bipolar disorder and their parents from 317 families.Main outcome measuresFamily-based association using FBAT and HBAT (http://www.biostat.harvard.edu/~fbat/default.html; Harvard School of Public Health, Boston, Massachusetts). Exploratory analyses testing for interactions of PPARD SNPs with clinical covariates and with other Wnt genes were conducted with GENASSOC (Stata Corp, College Station, Texas).ResultsIn the initial analysis, the most significantly associated SNP was rs2267665 in PPARD (nominal P < .001). This remained significant at P = .05 by permutation after accounting for all SNPs tested. Additional genotyping in PPARD yielded 4 SNPs in 1 haplotype block that were significantly associated with bipolar disorder (P < .01), the most significant being rs9462082 (P < .001). Exploratory analyses revealed significant evidence (P < .01) for interactions of rs9462082 with poor functioning on the Global Assessment Scale (odds ratio [OR], 3.36; 95% confidence interval [CI], 1.85-6.08) and with SNPs in WNT2B (rs3790606: OR, 2.56; 95% CI, 1.67-4.00) and WNT7A (rs4685048: OR, 1.79; 95% CI, 1.23-2.63).ConclusionsWe found evidence for association of bipolar disorder with PPARD, a gene in the Wnt signaling pathway. The consistency of this result with one from the Wellcome Trust Case-Control Consortium encourages further study. If the finding can be confirmed in additional samples, it may illuminate a new avenue for understanding the pathogenesis of severe bipolar disorder and developing more effective treatments.

Dataset Information

No evidence for association between 19 cholinergic genes and bipolar disorder.

Publications

No evidence for association between 19 cholinergic genes and bipolar disorder.

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