BDgene

Core Gene from Gene Prioritization Pathways from PBA (Pathway-based Analysis) Enriched Pathways for Core Genes Enriched Pathways for Cross-disorder Genes

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Study Report

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Basic Info

Reference	Etain, B.,2012 PMID: 22694957
Citation	Etain, B., A. Dumaine, et al. (2012). "Genetic and functional abnormalities of the melatonin biosynthesis pathway in patients with bipolar disorder." Hum Mol Genet.
Disease Type	Bipolar Disorder
Study Design	case-control
Study Type	Candidate-gene association study
Sample Size	345 patients with BD and 272 controls
SNP/Region/Marker Size	4 SNPs
Predominant Ethnicity	Caucasian
Population	French and German
Gender	Discovery sample:162 males and 197 females for BD patients;126 males and 94 females for controls.Replication sample:230 males and 250 females for BD patients;329 males and 343 females for controls.

Detail Info

Sample Diagnosis	DSM
Sample Status	Discovery sample:Three hundred and forty-five euthymic patients fulfilling DSM-IV criteria for BD type I or II were included into three French universityaffiliated psychiatry departments (Paris-Creteil, Bordeaux and Nancy) as described elsewhere. Two hundred and twenty controls without personal or first-degree relatives' history of affective disorders or suicidal behaviours were recruited among blood donors at the Pitie-Salpetriere and Henri Mondor Hospitals (France). All patients and controls were of French descent, with at least three grandparents from mainland France. Fifty-two additional healthy French controls, for whom few DNA was available, were sequenced only for the promoter region and used for association studies in order to increase statistical power. Replication sample:All patients received a DSM-IV diagnosis of BD. Four hundred and eighty patients were selected from a larger sample from Germany as previously described. Six hundred and seventy-two German controls were drawn from a pool of controls as described elsewhere. Controls were screened to exclude a diagnosis of BD.
Replication Size	480 patients with BD and 672 controls
Technique	Genotyping
Statistical Method	Statistical testing for allelic and haplotypic associations was carried out using the PLINK v1.07 software.
Result Summary	We performed an association study on this discovery sample using common variants located in the promoter region and showed that rs4446909 was significantly associated with BD (P= 0.01) and associated with a lower mRNA level (P< 10(-4)) and a lower enzymatic activity (P< 0.05) of ASMT. A replication study and a meta-analysis using 480 independent patients with BD and 672 controls confirmed the significant association between rs4446909 and BD (P= 0.002). These results correlate with the general lower ASMT enzymatic activity observed in patients with BD (P= 0.001) compared with controls. Finally, several deleterious ASMT mutations identified in patients were associated with low ASMT activity (P= 0.01). In this study, we determined how rare and common variations in ASMT might play a role in BD vulnerability and suggest a general role of melatonin as susceptibility factor for BD.

SNPs reported by this study for BD (count: 4)

SNP	Related Gene(s)	Allele Change	Risk Allele	Statistical Values	Author Comments	Result Category
rs6644635	ASMT		T	Allele association analysis: for French sample, P(value(Pc)=0.64(1), OR[95%CI]=1.06[0.84-1.33]; for German sample, P(value(Pc)=0.67(1), OR[95%CI]=0.96[0.80-1.15]; meta P(value=0.96, OR[95%CI]=1[0.87-1.15], Q=0.53	No significant association was observed in BD. No significant association was observed in BD.	Negative
rs4446909	ASMT		G	Allele association analysis: for French sample, P(value(Pc)=0.01(0.04), OR[95%CI]=1.38[1.07-1.76]; for German sample, P(value(Pc)=0.05(0.2), OR[95%CI]=1.22[1.00-1.48]; meta P(value=0.002, OR[95%CI]=1.28[1.09-1.49], Q=0.45	Significant association was observed in BD. Significant association was observed in BD.	Positive
rs56690322	ASMT		A	Allele association analysis: for French sample, P(value(Pc)=0.03(0.2), OR[95%CI]=1.48[1.03-2.13]; for German sample, P(value(Pc)=0.63(1), OR[95%CI]=1.08[0.79-1.46]; meta P(value=0.17, OR[95%CI]=1.23[0.98-1.55], Q=0.18	Significant association was observed in BD. Significant association was observed in BD.	Positive
rs5989681	ASMT		G	Allele association analysis: for French sample, P(value(Pc)=0.05(0.13), OR[95%CI]=1.27[1.00-1.60]; for German sample, P(value(Pc)=0.07(0.27), OR[95%CI]=1.2[0.99-1.46]; meta P(value=0.008, OR[95%CI]=1.23[1.06-1.42], Q=0.73	Significant association was observed in BD. Significant association was observed in BD.	Positive

Haplotypes reported by this study for BD (count: 5)

Markers	Haplotype	Related Gene(s)/Region(s)	Statistical Values	Author Comments	Result Category
rs4446909 - rs5989681 - rs56690322 - rs6644635	G-G-G-T	ASMT	Haplotype association analysis:for French sample, P(value(Pperm)=0.33(0.85), OR[95%CI]=0.88[0.68-1.14]; for German sample, P(value(Pperm)=1(1), OR[95%CI]=1[0.83-1.21]; meta P(value=0.56, OR[95%CI]=0.96[0.82-1.11]	No significant association was observed in BD. No significant association was observed in BD.	Negative
rs4446909 - rs5989681 - rs56690322 - rs6644635	A-C-G-C	ASMT	Haplotype association analysis:for French sample, P(value(Pperm)=0.007(0.03), OR[95%CI]=0.71[0.55-0.91]; for German sample, P(value(Pperm)=0.02(0.14), OR[95%CI]=0.79[0.64-0.97]; meta P(value=0.0005, OR[95%CI]=0.76[0.65-0.89]	Significant association was observed in BD. Significant association was observed in BD.	Positive
rs4446909 - rs5989681 - rs56690322 - rs6644635	G-G-G-C	ASMT	Haplotype association analysis:for French sample, P(value(Pperm)=0.11(0.46), OR[95%CI]=1.23[0.95-1.59]; for German sample, P(value(Pperm)=0.1(0.39), OR[95%CI]=1.17[0.97-1.41]; meta P(value=0.02, OR[95%CI]=1.19[1.03-1.38]	Significant association was observed in BD. Significant association was observed in BD.	Positive
rs4446909 - rs5989681 - rs56690322 - rs6644635	G-G-A-T	ASMT	Haplotype association analysis:for French sample, P(value(Pperm)=0.07(0.3), OR[95%CI]=1.43[0.98-2.09]; for German sample, P(value(Pperm)=0.48(1), OR[95%CI]=0.89[0.65-1.21]; meta P(value=0.54, OR[95%CI]=1.08[0.85-1.37]	No significant association was observed in BD. No significant association was observed in BD.	Negative
rs4446909 - rs5989681 - rs56690322 - rs6644635	G-C-G-C	ASMT	Haplotype association analysis:for French sample, P(value(Pperm)=0.37(0.85), OR[95%CI]=1.24[0.77-1.99]; for German sample, P(value(Pperm)=0.06(0.36), OR[95%CI]=1.5[0.98-2.30]; meta P(value=0.05, OR[95%CI]=1.37[1.00-1.89]	No significant association was observed in BD. No significant association was observed in BD.	Negative

Genes reported by this study for BD (count: 1)