Project

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Copy number variants in bipolar affective disorder

Applicant Aubry Jean-Michel
Number 125469
Funding scheme Project funding
Research institution Consultation Eaux-Vives Institution universitaire genevoise de psychiatrie
Institution of higher education University of Geneva - GE
Main discipline Neurology, Psychiatry
Start/End 01.05.2009 - 31.12.2011
Approved amount 347'458.00
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Keywords (7)

bipolar disorders; copy number variants; Genomic rearrangements; genetic susceptibility; genetic; CNV; neurodevelopmental

Lay Summary (English)

Lead
Lay summary
Copy number variants in bipolar affective disorderJean-Michel Aubry, Alexandre Dayer, Michel Guipponi, Stylianos Antonarakis, Alain MalafosseBipolar affective disorder (BPAD) is a severe psychiatric condition characterized by mood swings and concerning at least 2-3% of the population. The precise causes of bipolar disorder has not been unraveled yet but recurrent genetic studies have shown that BPAD and schizophrenia share common genetic susceptibility genes. Genomic rearrangements such as the so-called copy number variants (CNVs) underlie several neurodevelopmental syndromes including mental retardation and autism. More recently, rare CNVs have been shown to be associated to schizophrenia, disrupting multiples genes in neurodevelopmental pathways. Given the recent evidence of an association between schizophrenia and rare CNVs, it is urgent to examine the role of CNVs in BPAD. The hypothesis that CNVs could be associated to at least some forms of BPAD will be tested. Furthermore, as recently shown in schizophrenia, it should be determined whether rare CNVs could also preferentially disrupt genes involved in brain development in BPAD.A first cohort composed of 455 BPAD probants and 65 BPAD relatives recruited in Geneva and Lausanne as well as 513 controls (collected through the center for blood transfusion in Geneva) is currently analyzed at the Centre National de Génotypage (Paris, France). A second independent cohort composed of 200 BPAD patients treated at the University of Geneva outpatient bipolar program and 200 well-matched controls will be collected in 2009-2010. This project will help deciphering the genetic and neurobiology complexity of bipolar disorder. It could allow the identification of highly penetrant variants that may be useful for genetic counseling. It could help identify individuals at high risk for BPAD and lead to new treatment strategies. Ultimately it will pave the way for the development of new clinical classifications in psychiatry based on genetic etiology. Our DNA collections and CNV data will also be available for larger multicentric international projects in the future.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Associated projects

Number Title Start Funding scheme
128379 Molecular control of limbic cortical circuit formation: a translational approach to stress-related disorders 01.10.2010 SNSF Professorships

Abstract

1.SUMMARYBackground: Bipolar affective disorder (BPAD) is a severe psychiatric condition with a strong heritability (?80%) and sharing common susceptibility genes with schizophrenia. Genomic rearrangements such as copy number variants (CNVs) underlie several neurodevelopmental syndromes including mental retardation and autism (Lee and Lupski, 2006) (Sebat et al., 2007, Weiss et al., 2008). More recently rare CNVs have been shown to be associated to schizophrenia (Stefansson et al., 2008, Stone et al., 2008, Xu et al., 2008) disrupting multiples genes in neurodevelopmental pathways (Walsh et al., 2008).Working hypothesis: Recurrent genetic studies have shown that BPAD and schizophrenia share common genetic susceptibility genes. Given the recent evidence of an association between schizophrenia and rare CNVs, it is urgent to examine the role of CNVs in BPAD. The hypothesis that CNVs could be associated to at least some forms of BPAD should be tested. Furthermore, as recently shown in schizophrenia, it should be determined whether rare CNVs could also preferentially disrupt genes involved in brain development in BPAD.Specific aims and methods:To achieve a comprehensive understanding of the genetic architecture that underlie susceptibility to BPAD, we propose to examine the role of CNVs in BPAD on a genome-wide scale in 2 separate cohorts of patients and controls. We will examine the association of common CNVs with BPAD susceptibility and make an effort to identify rare BPAD-specific genomic variants. A first cohort composed of 455 BPAD probands and 65 BPAD relatives recruited in Geneva and Lausanne as well as 513 controls (collected through the center for blood transfusion in Geneva) is currently analyzed using the Illumina human 610K arrays at the Centre National de Génotypage (Paris, France). A second independent cohort composed of 200 BPAD patients treated at the Geneva University Hospitals outpatient bipolar program and 200 well-matched controls will be collected in 2009-2010. This second cohort will be screened using the same Illumina human 610K arrays at the NCCR “Frontiers in Genetics” Genomic platform (CMU, Geneva). Detected CNVs will be subsequently confirmed and refined using alternative methods including comparative genomic hybridization (array CGH), Real-Time PCR and/or multiple probe ligation assay (MLPA). CNVs will be examined for association with BPAD according to type, size, number and mean CNV load using gene count. Genes affected by CNVs exclusively found or significantly more present in BPAD patients than controls will be functionally classified to investigate the hypothesis that neurodevelopmental pathways are preferentially disrupted in BPAD. Expected value of the proposed project:This project will help deciphering the genetic and neurobiology complexity of bipolar disorder. It could allow the identification of highly penetrant variants that may be useful for genetic counseling. It could help identify individuals at high risk for BPAD and lead to new treatment strategies. Ultimately it will pave the way for the development of new clinical classifications in psychiatry based on genetic etiology. Our DNA collections and CNV data will also be available for larger multicentric international projects in the future.
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