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Comprehensive genetic analysis of a series of large families affected with bipolar disorder

English title Comprehensive genetic analysis of a series of large families affected with bipolar disorder
Applicant Cichon Sven
Number 156791
Funding scheme Project funding (Div. I-III)
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Basel - BS
Main discipline Neurophysiology and Brain Research
Start/End 01.06.2015 - 31.05.2019
Approved amount 599'508.00
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Keywords (5)

rare risk variants; bipolar disorder; whole exome sequencing; next-generation resequencing; di-genic and multi-genic effects

Lay Summary (German)

Lead
Die bipolare Störung (auch manisch-depressive Erkrankung genannt) ist eine psychiatrische Erkrankung, die durch einen episodischen Verlauf mit depressiven, manischen bzw. hypomanischen oder gemischten Phasen gekennzeichnet ist. Genetische Faktoren tragen neben Umweltfaktoren zur Krankheitsentstehung bei. Bisher sind die erblichen Faktoren, die zur Entstehung der Erkrankung beitragen, nur unzureichend bekannt. Das Projekt leistet zu ihrer Identifizierung einen Beitrag.
Lay summary

Inhalt und Ziele des Forschungsprojekts

Bereits in der Antike wurde die bipolare Störung beschrieben. Für die betroffenen Menschen gleicht das Leben einer Achterbahn, gefangen im extremen Gefühlsspektrum zwischen grenzenloser Euphorie (Manie) und absolutem Tief (Depression). Die Krankheit gehört, mit einem Lebenszeitrisiko von 0,5-1,5% weltweit, zu den häufigen neuropsychiatrischen Störungen. Zu ihrer Entstehung tragen neben Umweltfaktoren substantiell auch genetische Faktoren bei. Um die biologischen Grundlagen der Krankheitsentstehung besser verstehen zu können, ist die Identifizierung dieser genetischen Risikofaktoren ein sehr wichtiger Schri

Besonders vielversprechend erscheint in diesem Zusammenhang die genetische Untersuchung grosser Mehrgenerationenfamilien mit mehreren an einer bipolaren Störung erkrankten Angehörigen. In dem vorliegenden Projekt werden wir 20 Familien aus Andalusien/Südspanien mittels neuer DNA-Sequenzierverfahren (sog. Exom-Sequenzierung) untersuchen und wollen dadurch genetische Veränderungen identifizieren, die in diesen Familien zur Krankheitsentstehung beitragen.

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Das Projekt befasst sich mit psychiatrisch-genetischer Grundlagenforschung. Die enormen Fortschritte der molekularen Humangenetik ermöglichen es heute, das Genom des Menschen systematisch nach genetischen Varianten und Mutationen zu durchsuchen, die sich zwischen Erkrankten und nicht-Erkrankten unterscheiden. Die identifizierten Genvarianten sollen zu den biologischen Prozessen führen, die an der Krankheitsentstehung beteiligt sind. Im Falle der bipolaren Störung stellt ein besseres Verständnis der Krankheitsmechanismen einen wichtigen Schritt hin zur Entwicklung besser wirksamer Therapien dar.

Keywords

bipolar disorder, rare risk variants, whole exome sequencing, di-genic and multi-genic effects, next-generation resequencing

Direct link to Lay Summary Last update: 08.05.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
Bipolar multiplex families have an increased burden of common risk variants for psychiatric disorders
Andlauer Till F. M., Guzman-Parra Jose, Streit Fabian, Strohmaier Jana, Gonzalez Maria Jose, Gil Flores Susana, Cabaleiro Fabeiro Francisco J., del Río Noriega Francisco, Perez Fermin Perez, Haro González Jesus, Orozco Diaz Guillermo, de Diego-Otero Yolanda, Moreno-Küstner Berta, Auburger Georg, Degenhardt Franziska, Heilmann-Heimbach Stefanie, Herms Stefan, Hoffmann Per, Frank Josef, Foo Jerome C., Treutlein Jens, Witt Stephanie H., Cichon Sven, Kogevinas Manolis, et al. (2019), Bipolar multiplex families have an increased burden of common risk variants for psychiatric disorders, in Molecular Psychiatry.
Genome-wide association study identifies 30 loci associated with bipolar disorder
Stahl Eli A., Breen Gerome, Forstner Andreas J., McQuillin Andrew, Ripke Stephan, Trubetskoy Vassily, Mattheisen Manuel, Wang Yunpeng, Coleman Jonathan R. I., Gaspar Héléna A., de Leeuw Christiaan A., Steinberg Stacy, Pavlides Jennifer M. Whitehead, Trzaskowski Maciej, Byrne Enda M., Pers Tune H., Holmans Peter A., Richards Alexander L., Abbott Liam, Agerbo Esben, Akil Huda, Albani Diego, Alliey-Rodriguez Ney, Als Thomas D., et al. (2019), Genome-wide association study identifies 30 loci associated with bipolar disorder, in Nature Genetics, 51(5), 793-803.
El estudio Andalusian Bipolar Family (ABiF): protocolo y descripción de la muestra
Guzman-Parra Jose, Rivas Fabio, Strohmaier Jana, Forstner Andreas, Streit Fabian, Auburger Georg, Propping Peter, Orozco-Diaz Guillermo, González Maria José, Gil-Flores Susana, Cabaleiro-Fabeiro Francisco Javier, del Río-Noriega Francisco, Perez-Perez Fermin, Haro-González Jesus, de Diego-Otero Yolanda, Romero-Sanchiz Pablo, Moreno-Küstner Berta, Cichon Sven, Nöthen Markus M., Rietschel Marcella, Mayoral Fermin (2018), El estudio Andalusian Bipolar Family (ABiF): protocolo y descripción de la muestra, in Revista de Psiquiatría y Salud Mental, 11(4), 199-207.
Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes
Ruderfer Douglas M., Ripke Stephan, McQuillin Andrew, Boocock James, Stahl Eli A., Pavlides Jennifer M. Whitehead, Mullins Niamh, Charney Alexander W., Ori Anil P.S., Loohuis Loes M. Olde, Domenici Enrico, Di Florio Arianna, Papiol Sergi, Kalman Janos L., Trubetskoy Vassily, Adolfsson Rolf, Agartz Ingrid, Agerbo Esben, Akil Huda, Albani Diego, Albus Margot, Alda Martin, Alexander Madeline, Alliey-Rodriguez Ney, et al. (2018), Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes, in Cell, 173(7), 1705-1715.e16.
Analysis of the Influence of microRNAs in Lithium Response in Bipolar Disorder
Reinbold Céline S., Forstner Andreas J., Hecker Julian, Fullerton Janice M., Hoffmann Per, Hou Liping, Heilbronner Urs, Degenhardt Franziska, Adli Mazda, Akiyama Kazufumi, Akula Nirmala, Ardau Raffaella, Arias Bárbara, Backlund Lena, Benabarre Antonio, Bengesser Susanne, Bhattacharjee Abesh K., Biernacka Joanna M., Birner Armin, Marie-Claire Cynthia, Cervantes Pablo, Chen Guo-Bo, Chen Hsi-Chung, Chillotti Caterina, et al. (2018), Analysis of the Influence of microRNAs in Lithium Response in Bipolar Disorder, in Frontiers in Psychiatry, 9, 207.
Identification of shared risk loci and pathways for bipolar disorder and schizophrenia
Forstner Andreas J., Hecker Julian, Hofmann Andrea, Maaser Anna, Reinbold Céline S., Mühleisen Thomas W., Leber Markus, Strohmaier Jana, Degenhardt Franziska, Treutlein Jens, Mattheisen Manuel, Schumacher Johannes, Streit Fabian, Meier Sandra, Herms Stefan, Hoffmann Per, Lacour André, Witt Stephanie H., Reif Andreas, Müller-Myhsok Bertram, Lucae Susanne, Maier Wolfgang, Schwarz Markus, Vedder Helmut, et al. (2017), Identification of shared risk loci and pathways for bipolar disorder and schizophrenia, in PLOS ONE, 12(2), e0171595-e0171595.

Collaboration

Group / person Country
Types of collaboration
Psychiatric Genomics Consortium United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Forschergruppe "IntegraMent" Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Neuroscience Network Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Quantitative Genomics Facility (QGF) Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Abteilung für Epidemiologie in der Psychiatrie, ZI Seelische Gesundheit Mannheim, Deutschland Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Jahrestagung der Deutschen Gesellschaft für Humangenetik (gfh) 2018 Talk given at a conference Comprehensive Genetic Analysis Of Whole Genome Sequencing Data From 108 Individuals Of 8 Multigenerational Spanish Families Affected With Bipolar Disorder 14.03.2019 Münster, Germany Fischer Sascha; Forstner Andreas; Cichon Sven;
World Congress of Psychiatric Genetics Poster Whole-genome sequencing of 108 individuals in a set of 8 extended families of Spanish origin 11.10.2018 Glasgow, Great Britain and Northern Ireland Forstner Andreas; Fischer Sascha; Cichon Sven;
Jahrestagung der Schweizerischen Gesellschaft für Medizinische Genetik (SGMG) Talk given at a conference Whole exome sequencing of 81 individuals from 27 multiply affected bipolar disorder families 13.04.2018 Bern, Switzerland Fischer Sascha; Forstner Andreas; Cichon Sven;
8th Grainau Workshop of Genetic Epidemiology, 2018, From Association to Function Talk given at a conference Genetics of affective disorders and schizophrenia: the picture 10 years after the first GWAS 11.04.2018 Grainau, Austria Forstner Andreas; Fischer Sascha; Cichon Sven;
Jahrestagung der Deutschen Gesellschaft für Humangenetik (gfh) 2018 Poster Analysis of microRNAs in Lithium Response in Bipolar Disorder 14.03.2018 Münster, Germany Cichon Sven; Forstner Andreas;
Human Brain Project Workshop - Brain medicine for non-specialists Talk given at a conference A manic-depressive history: the genetic dissection of complex neuropsychiatric disorders 06.07.2017 Innsbruck, Austria Cichon Sven;


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Diskussionsveranstaltung "Mensch nach Mass" German-speaking Switzerland Western Switzerland 2019

Associated projects

Number Title Start Funding scheme
182731 Towards a mechanistic understanding of common and rare genetic risk variants for bipolar disorder: studies in iPSC models and extended families 01.11.2020 Project funding (Div. I-III)

Abstract

Aim of the project: The aim of the proposed project is to improve understanding of the complex genetic causes of bipolar affective disorder by identifying highly penetrant risk genes or combinations of risk variants in a unique set of 20 extended and multiply affected families with bipolar disorder originating from Andalusia in Southern Spain. To reach this aim, we propose a combination of whole exome sequencing in several affected individuals as well as selected unaffected individuals and high-density SNP arrays to enable a comprehensive bioinformatic and statistical analysis. The most promising 40 risk genes will be followed-up by next-generation resequencing in a series of 1260 unrelated patients with bipolar disorder, comprising 300 patients from Spain and 960 patients from Germany. Background and rationale: Bipolar disorder is a common neuropsychiatric disorder with a life-time prevalence of 0.5 - 1.5% in all populations worldwide and an estimated heritability of 60-80%. Previous work, including our own, provides evidence that the heritable part of bipolar disorder is comprised of a mutational spectrum ranging from “common low-penetrance” to “rare high-penetrance”. In the psychiatric genetics field the identification of rare variants with higher penetrance is considered a particularly promising area of research since they would allow insights into a so far less well studied portion of the heritability, and they could prove more amenable to subsequent biological investigation. Systematic, exome-wide sequencing efforts in bipolar disorder using next-generation sequencing technology have only recently been launched by different international groups. Studies in unrelated (and often sporadic) cases are complicated by substantial locus and allelic heterogeneity. For the proposed project, we have favoured the analysis of multiply affected families as an alternative approach. Monitoring of co-segregation with disease in each family provides a useful tool for distinguishing disease-related from rare neutral variation. In particular, we will comprehensively exploit the exceptional genetic information content of a series of large families with bipolar disorder from a confined region in Andalusia/Spain. We propose to sequence on average 10 individuals per family which is more than in many other “standard” family-based exome-sequencing projects. We argue that this strategy will strongly increase the power to detect individual gene variants of higher penetrance as well as di- and multigenic effects because it is less hampered by the presence of phenocopies. In sequencing studies looking at few individuals per family (e.g. 3 affecteds), true risk variants are likely to be missed if one of the sequenced individuals is not a carrier of that variant. Apart from this, it will also allow us to compare the genome-wide load of rare coding variants between affected and unaffected family members and how rare variants interact with each other. Genome-wide SNP data will provide opportunities to investigate the influence of copy number variants (CNVs) as well as polygenic risk scores on the penetrance of rare risk variants segregating in the families.Relevance and impact: In view of the large impact of bipolar disorder on the global burden of disease, it is important that basic research into this disorder will be performed. The identification of risk genes with large effects has now become feasible through next-generation sequencing technology and the use of suitable, large and multiply affected families. We anticipate that the results of our study will make an important contribution to understanding the biological foundations of bipolar disorder which is generally seen as a first step to developing new therapies.
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