Genome-wide scan for genes involved in bipolar affective disorder in 70 European families ascertained through a bipolar type I early-onset proband: supportive evidence for linkage at 3p14

Étain, Bruno; Mathieu, Flavie; Rietschel, Marcella; Maier, Wolfgang; Albus, Margot; McKeon, Patrick O.; Roche, Siobhan; Kealey, Carmel; Blackwood, Douglas; Muir, Walter; Bellivier, Frank; Henry, Chantal; Dina, Christian; Gallina, Sophie; Gurling, Hugh; Malafosse, Alain; Preisig, Martin; Ferrero, François; Cichon, Sven; Schumacher, Johannes; Ohlraun, Stephanie; Borrmann-Hassenbach, Margitta; Propping, Peter; Jamra, Rami Abou; Schulze, Thomas G.; Marusic, A; Dernovsek, Z M; Giros, Bruno; Bourgeron, Thomas; Lemainque, Arnaud; Bacq, Delphine; Bétard, Christine; Charon, Céline; Nöthen, Markus M.; Lathrop, Mark; Leboyer, Marion

doi:10.1038/sj.mp.4001815

Cited by 70 publications

(48 citation statements)

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“…This association was not observed when considering late-onset BD, suggesting that this susceptibility variant might be involved only in the early-onset subgroup of patients. These results are consistent with those of our previous genomewide scan for early-onset BD, 8 and strengthened by three other genome-wide scans reporting linkage on chromosome 20p12. [9][10][11] The SNP, for which the highest significant association was observed (SNP4), is located in a CpG island, spanning the promoter region of the gene, and may affect the transcription level of SNAP25.…”

Section: Discussionsupporting

confidence: 92%

“…7 We recently carried out a whole-genome linkage analysis in early-onset BD sibpairs, and identified six regions with a suggestive multipoint nonparametric logarithm of the odds ratio-score. 8 These regions included the 20p12 region, already reported by three independent studies to contain a gene conferring susceptibility to BD. [9][10][11] The gene encoding the synaptosomal-associated protein of 25 kDa (SNAP25) is located in this region.…”

Section: Introductionmentioning

confidence: 99%

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A SNAP25 promoter variant is associated with early-onset bipolar disorder and a high expression level in brain

et al. 2009

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Bipolar disorder (BD) is one of the most common and persistent psychiatric disorders. Earlyonset BD has been shown to be the most severe and familial form. We recently carried out a whole-genome linkage analysis on sibpairs affected by early-onset BD and showed that the 20p12 region was more frequently shared in our families than expected by chance. The synaptosomal-associated protein SNAP25 is a presynaptic plasma membrane protein essential for the triggering of vesicular fusion and neurotransmitter release, and for which abnormal protein levels have been reported in postmortem studies of bipolar patients. We hypothesised that variations in the gene encoding SNAP25, located on chromosome 20p12, might influence the susceptibility to early-onset BD. We screened SNAP25 for mutations and performed a case-control association study in 197 patients with early-onset BD, 202 patients with late-onset BD and 136 unaffected subjects. In addition, we analysed the expression level of the two SNAP25 isoforms in 60 brains. We showed that one variant, located in the promoter region, was associated with early-onset BD but not with the late-onset subgroup. In addition, individuals homozygous for this variant showed a significant higher SNAP25b expression level in prefrontal cortex. These results show that variations in SNAP25, associated with an increased gene expression level in prefrontal cortex, might predispose to early-onset BD. Further analyses of this gene, as well as analysis of genes encoding for the SNAP25 protein partners, are required to understand the impact of such molecular mechanisms in BD.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

A SNAP25 promoter variant is associated with early-onset bipolar disorder and a high expression level in brain

et al. 2009

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“…The ascertainment scheme is detailed elsewhere (Etain et al, 2006). Families were included on the basis of a BP type I proband who suffered one or more thymic episodes before the age of 22 years, and an affected sibling suffering from either BP type I or II (regardless of AAO) or single or recurrent early-onset major depressive episode.…”

Section: Subjectsmentioning

confidence: 99%

“…Through a European Collaborative Study (France, Germany, Ireland, Scotland, Switzerland, England, Slovenia) (Etain et al, 2006), we previously carried out a genome-wide linkage analysis. Two phenotypes were analyzed: a "narrow phenotype" (EO-BPI only) and a "broad phenotype" (including as affected, siblings suffering from either BPI or BPII regardless of AAO, or Major Depressive Episode (MDE) with an early onset).…”

Section: Introductionmentioning

confidence: 99%

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European collaborative study of early‐onset bipolar disorder: Evidence for genetic heterogeneity on 2q14 according to age at onset

Mathieu

Dizier

Étain

et al. 2010

American J of Med Genetics Pt B

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Bipolar disorder has a genetic component, but the mode of inheritance remains unclear. A previous genome scan conducted in 70 European families led to detect eight regions linked to bipolar disease. Here, we present an investigation of whether the phenotypic heterogeneity of the disorder corresponds to genetic heterogeneity in these regions using additional markers and an extended sample of families. The MLS statistic was used for linkage analyses. The predivided sample test and the maximum likelihood binomial methods were used to test genetic homogeneity between early-onset bipolar type I (cut-off of 22 years) and other types of the disorder (later onset of bipolar type I and early-onset bipolar type II), using a total of 138 independent bipolar-affected sib-pairs. Analysis of the extended sample of families supports linkage in four regions (2q14, 3p14, 16p23, and 20p12) of the eight regions of linkage suggested by our previous genome scan. Heterogeneity testing revealed genetic heterogeneity between early and late-onset bipolar type I in the 2q14 region (P = 0.0001). Only the early form of the bipolar disorder but not the late form appeared to be linked to this region. This region may therefore include a genetic factor either specifically involved in the early-onset bipolar type I or only influencing the age at onset (AAO). Our findings illustrate that stratification according to AAO may be valuable for the identification of genetic vulnerability polymorphisms. (c) 2010 Wiley-Liss, Inc

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Meta-analysis of Genome-wide Association Studies for Neuroticism, and the Polygenic Association With Major Depressive Disorder

Moor¹,

et al. 2015

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Genome-wide scan for genes involved in bipolar affective disorder in 70 European families ascertained through a bipolar type I early-onset proband: supportive evidence for linkage at 3p14

Cited by 70 publications

References 46 publications

A SNAP25 promoter variant is associated with early-onset bipolar disorder and a high expression level in brain

A SNAP25 promoter variant is associated with early-onset bipolar disorder and a high expression level in brain

European collaborative study of early‐onset bipolar disorder: Evidence for genetic heterogeneity on 2q14 according to age at onset

Meta-analysis of Genome-wide Association Studies for Neuroticism, and the Polygenic Association With Major Depressive Disorder

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