Bipolar multiplex families have an increased burden of common risk variants for psychiatric disorders

Andlauer TF, Guzman-Parra J, González MJ, Gil Flores S, Cabaleiro Fabeiro FJ, del Río Noriega F, Perez FP, Haro González J, Orozco Diaz G, de Diego-Otero Y, Moreno-Küstner B, Auburger G, Heilmann-Heimbach S, Stahl EA, Breen G, Forstner AJ, McQuillin A, Ripke S, Mattheisen M, Coleman JR, Gaspar HA, de Leeuw CA, Pavlides JM, Pers TH, Holmans PA, Abbott L, Akil H, Albani D, Alliey-Rodriguez N, Als TD, Anjorin A, Antilla V, Awasthi S, Badner JA, Barchas JD, Bass N, Bauer M, Belliveau R, Bergen SE, Pedersen CB, Bøen E, Boks M, Boocock J, Budde M, Bunney W, Burmeister M, Bybjerg-Grauholm J, Byerley W, Casas M, Cerrato F, Cervantes P, Chambert K, Charney AW, Chen D, Churchhouse C, Coryell W, Craig DW, Cruceanu C, Czerski PM, Dale AM, de Jong S, Del-Favero J, DePaulo JR, Djurovic S, Dobbyn AL, Dumont A, Elvsåshagen T, Fan CC, Fischer SB, Flickinger M, Foroud TM, Forty L, Fraser C, Freimer NB, Frisén L, Gade K, Gage D, Garnham J, Giambartolomei C, Goldstein J, Gordon-Smith K, Green EK, Green MJ, Greenwood TA, Guan W, Parra JG, Hamshere ML, Hautzinger M, Heilbronner U, Hipolito M, Holland D, Huckins L, Jamain S, Johnson JS, Juréus A, Kandaswamy R, Karlsson R, Kennedy JL, Kittel-Schneider S, Knowles JA, Kogevinas M, Koller AC, Kupka R, Lavebratt C, Lawrence J, Lawson WB, Leber M, Lee PH, Levy SE, Li JZ, Liu C, Maaser A, Mahon PB, Martinsson L, McCarroll S, McGuffin P, McInnis MG, McKay JD, Medeiros H, Medland SE, Meng F, Milani L, Montgomery GW, Morris DW, Mühleisen TW, Mullins N, Nguyen H, Nievergelt CM, Adolfsson AN, Nwulia EA, O’Donovan C, Loohuis LM, Ori AP, Oruc L, Ösby U, Perry A, Pfennig A, Potash JB, Purcell SM, Regeer EJ, Reif A, Reinbold CS, Rice JP, Richards AL, Rivas F, Roussos P, Ruderfer DM, Ryu E, Sánchez-Mora C, Schatzberg AF, Scheftner WA, Schork NJ, Weickert CS, Shehktman T, Shilling PD, Sigurdsson E, Slaney C, Smeland OB, Sobell JL, Spijker AT, Clair DS, Steffens M, Strauss JS, Szelinger S, Thompson RC, EThorgeirsson T, Vedde H, Wang W, Watson SJ, Weickert TW, Xi S, Xu W, Young AH, Zandi P, Zhang P, Zollner S, Adolfsson R, Agartz I, Alda M, Backlund L, Baune BT, Bellivier F, Berrettini WH, Biernacka JM, Blackwood DH, Boehnke M, Børglum AD, Corvin A, Daly MJ, Dannlowski U, Esko T, Etain B, Frye M, Fullerton JM, Gershon ES, Gill M, Goes F, Grigoroiu-Serbanescu M, Hauser J, Hultman CM, Jones I, Jones LA, Kahn RS, Kirov G, Landén M, Leboyer M, Lewis CM, Lissowska J, Martin NG, Mayoral F, McElroy SL, McIntosh AM, McMahon FJ, Melle I, Metspalu A, Mitchell PB, Morken G, Mors O, Mortensen PB, Myers RM, Neale BM, Nimgaonkar V, Nöthen MM, O’Donovan MC, Oedegaard KJ, Owen MJ, Pato C, Pato MT, Ramos-Quiroga JA, Ribasés M, Rouleau GA, Schalling M, Schofield PR, Schulze TG, Serretti A, Stefansson H, Stefansson K, Stordal E, Sullivan PF, Turecki G, Vaaler AE, Vieta E, Vincent JB, Nurnberger JI, Wray NR, Florio AD, Edenberg HJ, Ophoff RA, Scott LJ, Andreassen OA, Kelsoe J, Sklar P, Trzaskowski M, Byrne EM, Abdellaoui A, Adams MJ, Agerbo E, Air TM, Bacanu SA, Bækvad-Hansen M, Beekman AT, Bigdeli TB, Binder EB, Bryois J, Buttenschøn HN, Bybjerg-Grauholm J, Cai N, Castelao E, Christensen JH, Clarke TK, Coleman JR, Colodro-Conde L, Couvy-Duchesne B, Craddock N, Crawford GE, Davies G, Deary IJ, Degenhardt F, Derks EM, Direk N, Dolan CV, Dunn EC, Eley TC, Escott-Price V, Kiadeh FFH, Finucane HK, Foo JC, Frank J, Goes FS, Gordon SD, Grove J, Hall LS, Hansen CS, Hansen TF, Herms S, Hickie IB, Hoffmann P, Homuth G, Horn C, Hottenga JJ, Hougaard DM, Howard DM, Ising M, Jansen R, Jorgenson E, Knowles JA, Kohane IS, Hill , Kraft J, Kretzschmar WW, Kutalik Z, Li Y, Lind PA, MacIntyre DJ, MacKinnon DF, Maier RM, Maier W, Marchini J, Mbarek H, McGrath P, McGuffin P, Mehta D, Middeldorp CM, Mihailov E, Milaneschi Y, Mondimore FM, Mostafavi S, Nauck M, Ng B, Nivard MG, Nyholt DR, O’Reilly PF, Oskarsson H, Painter JN, Pedersen MG, Peterson RE, Pettersson E, Peyrot WJ, Pistis G, Posthuma D, Quiroz JA, Qvist P, Riley BP, Rivera M, Mirza SS, Schoevers R, Schulte EC, Shen L, Shi J, Shyn SI, Sigurdsson E, Sinnamon GC, Smit JH, Smith DJ, Steinberg S, Streit F, Strohmaier J, Tansey KE, Teismann H, Teumer A, Thompson W, Thomson PA, Thorgeirsson TE, Traylor M, Treutlein J, Trubetskoy V, Uitterlinden AG, Umbricht D, Van der Auwera S, van Hemert AM, Viktorin A, Visscher PM, Wang Y, Webb BT, Weinsheimer SM, Wellmann J, Willemsen G, Witt SH, Wu Y, Xi HS, Yang J, Zhang F, Arolt V, Berger K, Boomsma DI, Cichon S, de Geus EJ, Domenici E, Domschke K, Grabe HJ, Hamilton SP, Hayward C, Heath AC, Kendler KS, Kloiber S, Lewis G, Li QS, Lucae S, Madden PA, Magnusson PK, Müller-Myhsok B, Nordentoft M, O’Donovan MC, Paciga SA, Pedersen NL, Penninx BW, Perlis RH, Porteous DJ, Potash JB, Preisig M, Rietschel M, Schaefer C, Schulze TG, Smoller JW, Tiemeier H, Uher R, Völzke H, Weissman MM, Werge T, Levinson DF, Rivas F, Müller-Myhsok B (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Book Volume: 26

Pages Range: 1286-1298

Journal Issue: 4

DOI: 10.1038/s41380-019-0558-2

Abstract

Multiplex families with a high prevalence of a psychiatric disorder are often examined to identify rare genetic variants with large effect sizes. In the present study, we analysed whether the risk for bipolar disorder (BD) in BD multiplex families is influenced by common genetic variants. Furthermore, we investigated whether this risk is conferred mainly by BD-specific risk variants or by variants also associated with the susceptibility to schizophrenia or major depression. In total, 395 individuals from 33 Andalusian BD multiplex families (166 BD, 78 major depressive disorder, 151 unaffected) as well as 438 subjects from an independent, BD case/control cohort (161 unrelated BD, 277 unrelated controls) were analysed. Polygenic risk scores (PRS) for BD, schizophrenia (SCZ), and major depression were calculated and compared between the cohorts. Both the familial BD cases and unaffected family members had higher PRS for all three psychiatric disorders than the independent controls, with BD and SCZ being significant after correction for multiple testing, suggesting a high baseline risk for several psychiatric disorders in the families. Moreover, familial BD cases showed significantly higher BD PRS than unaffected family members and unrelated BD cases. A plausible hypothesis is that, in multiplex families with a general increase in risk for psychiatric disease, BD development is attributable to a high burden of common variants that confer a specific risk for BD. The present analyses demonstrated that common genetic risk variants for psychiatric disorders are likely to contribute to the high incidence of affective psychiatric disorders in the multiplex families. However, the PRS explained only part of the observed phenotypic variance, and rare variants might have also contributed to disease development.

Involved external institutions

Icahn School of Medicine at Mount Sinai United States (USA) (US) Virginia Commonwealth University (VCU) United States (USA) (US) Max-Planck-Institut für Psychiatrie (Deutsche Forschungsanstalt für Psychiatrie) Germany (DE) Lundbeck Foundation Initiative for Integrative Psychiatric Research Denmark (DK) University of Edinburgh United Kingdom (GB) Wellcome Trust Sanger Institute - Genome Research Limited United Kingdom (GB) Aarhus University Denmark (DK) Washington University in St. Louis United States (USA) (US) Pfizer, Inc. United States (USA) (US) Karolinska Institute Sweden (SE) University of Iowa United States (USA) (US) Lausanne University Hospital / Centre hospitalier universitaire vaudois (CHUV) Switzerland (CH) Universitätsklinikum Mannheim / University Medical Centre Mannheim (Universitätsmedizin Mannheim) Germany (DE) deCODE genetics Iceland (IS) Namsos Hospital Norway (NO) St. Olavs University Hospital / St. Olavs Hospital Universitetssykehuset i Trondheim Norway (NO) Indiana University – Purdue University Indianapolis United States (USA) (US) University of Michigan United States (USA) (US) University of Queensland Australia (AU) Klinikum der Universität München (LMU Klinikum) Germany (DE) Johns Hopkins Hospital United States (USA) (US) Howard University Hospital (HUH) / Freedmen's Hospital United States (USA) (US) Rigshospitalet Denmark (DK) Universitätsklinikum Bonn Germany (DE) F. Hoffmann-La Roche Ltd Switzerland (CH) University of Amsterdam Netherlands (NL) University Of Worcester United Kingdom (GB) University of New South Wales (UNSW) Australia (AU) Eli and Edythe L. Broad Institute of MIT and Harvard United States (USA) (US) Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM) Spain (ES) McGill University Canada (CA) Karolinska University Hospital / Karolinska Universitetssjukhuset Sweden (SE) University of Bologna / Università di Bologna Italy (IT) Universitat de Barcelona (UB) / University of Barcelona Spain (ES) Cardiff University United Kingdom (GB) Institut universitaire de médecine sociale et préventive (IUMSP) Switzerland (CH) Wellcome Centre for Human Genetics United Kingdom (GB) Medical Research Council United Kingdom (GB) University Medical Centre Utrecht (UMC Utrecht) Netherlands (NL) Oslo University Hospital / Oslo Universitetssykehus Rikshospitalet Norway (NO) King’s College London United Kingdom (GB) University of Adelaide Australia (AU) University Medical Center Groningen (UMCG) / Universitair Medisch Centrum Groningen Netherlands (NL) Westfälische Wilhelms-Universität (WWU) Münster Germany (DE) Universitätsmedizin Greifswald / Universitätsklinikum Greifswald Germany (DE) Hospital Regional de Málaga Spain (ES) NTNU Trondheim - Norwegian University of Science and Technology Norway (NO) Dalhousie University Canada (CA) University of California Los Angeles (UCLA) United States (USA) (US) McGill University Health Centre (MUHC) / Centre universitaire de santé McGill Canada (CA) Peninsula College of Medicine and Dentistry (PCMD) United Kingdom (GB) University of California, San Diego (UC San Diego, UCSD) United States (USA) (US) University of Minnesota (UMN) United States (USA) (US) Poznan University of Medical Sciences / Uniwersytet Medyczny im. Karola Marcinkowskiego w Poznaniu Poland (PL) Eberhard Karls Universität Tübingen Germany (DE) Amsterdam University Medical Centers (Amsterdam UMC) / Amsterdam Universitair Medische Centra Netherlands (NL) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) Erasmus University Medical Center (MC) Netherlands (NL) Universitäre Psychiatrische Kliniken Basel (UPK) / Universitäre Psychiatrische Kliniken Base Switzerland (CH) Massachusetts General Hospital United States (USA) (US) Altrecht Netherlands (NL) Harvard T.H. Chan School of Public Health United States (USA) (US) Universität Basel Switzerland (CH) University of California San Francisco (UCSF) United States (USA) (US) Charité - Universitätsmedizin Berlin Germany (DE) Vanderbilt University United States (USA) (US) Mayo Clinic United States (USA) (US) Stanford University United States (USA) (US) Assistance Publique-Hôpitaux de Paris (AP-HP) France (FR) University of Chicago United States (USA) (US) Trinity College Dublin Ireland (IE) Lindner Center of HOPE United States (USA) (US) Haukeland University Hospital / Haukeland universitetssykehus Norway (NO) Centre for Addiction and Mental Health (CAMH) Canada (CA) University of British Columbia Canada (CA) University of Sydney (USYD) Australia (AU) Diakonhjemmet Hospital Norway (NO) University of California Irvine United States (USA) (US) University of Pittsburgh United States (USA) (US) Kaiser Permanente United States (USA) (US) James Cook University Australia (AU) University of Glasgow United Kingdom (GB) Columbia University Irving Medical Center (CUIMC) United States (USA) (US) Munich Cluster for Systems Neurology (SyNergy) Germany (DE) Universitätsklinikum Freiburg Germany (DE) Università degli Studi di Trento Italy (IT) University College London (UCL) United Kingdom (GB) Janssen Global Services, LLC United States (USA) (US) HudsonAlpha United States (USA) (US) University of Illinois at Chicago United States (USA) (US) Johns Hopkins University (JHU) United States (USA) (US) Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM) / Federal Institute for Drugs and Medical Devices Germany (DE) University of Toronto Canada (CA) Psychiatrisches Zentrum Nordbaden / Psychiatric Center Nordbaden Germany (DE) Umeå University Sweden (SE) University of Southern California (USC) United States (USA) (US) Neuroscience Research Australia NeuRA Australia (AU) Université Paris Cité France (FR) National Institute of Mental Health Information Resource Center United States (USA) (US) University of Tartu Estonia (EE) Indiana University United States (USA) (US) The Jane and Terry Semel Institute for Neuroscience and Human Behavior United States (USA) (US) North East London NHS Foundation Trust United Kingdom (GB) University of Galway (NUIG) / Ollscoil na Gaillimhe Ireland (IE) University of Sarajevo Bosnia And Herzegovina (BA) PsyQ Netherlands (NL) University of Aberdeen United Kingdom (GB) University of Pennsylvania (UPenn) United States (USA) (US) Rheinische Friedrich-Wilhelms-Universität Bonn Germany (DE) Universitätsklinikum Carl Gustav Carus Dresden Germany (DE) Vrije Universiteit Amsterdam (VU) / University Amsterdam Netherlands (NL) Hospital Universitario Puerto Real Spain (ES) Hospital Universitario Reina Sofía de Córdoba Edificio IMIBIC Spain (ES) University Hospital of Jaén Spain (ES) Universitätsklinikum Frankfurt am Main (KGU) Germany (DE) Instituto de Salud Global de Barcelona (ISGlobal) Spain (ES) Hospital Punta de Europa Spain (ES) National Institute for Health and Medical Research / Institut national de la santé et de la recherche médicale (INSERM) France (FR) Universidad de Málaga / University of Malaga Spain (ES) Goethe-Universität Frankfurt am Main Germany (DE) Hospital Universitario de Jerez Spain (ES) Berkshire Healthcare NHS Foundation Trust United Kingdom (GB) Rush University United States (USA) (US) Mario Negri Institute for Pharmacological Research (IRCCS) / Istituto di Ricerche Farmacologiche Mario Negri Italy (IT) Weill Cornell Medicine United States (USA) (US) Universitätsklinikum Köln Germany (DE) University of Iowa Hospitals and Clinics (UIHC) United States (USA) (US) Translational Genomics Research Institute (TGen) United States (USA) (US) University of Antwerp / Universiteit Antwerpen Belgium (BE) Oslo University Hospital, Ullevål / Oslo universitetssykehus, Ullevål Norway (NO) University of Iceland (UI) / Háskóli Íslands Iceland (IS) Princess Margaret Cancer Centre / Princess Margaret Hospital Canada (CA) Maria Skłodowska-Curie Institute of Oncology / Centrum Onkologii–Instytut im. Marii Skłodowskiej-Curie w Warszawie Poland (PL) Scripps Research Institute (TSRI) United States (USA) (US) Harvard University United States (USA) (US) NHS Scotland - Scotland's Health on the Web United Kingdom (GB) Queensland University of Technology (QUT) Australia (AU) Solid Biosciences Inc. United States (USA) (US) Duke University United States (USA) (US) University of Oxford United Kingdom (GB) Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK e.V.) Germany (DE) University of Cambridge United Kingdom (GB) National Cancer Institute (NCI) United States (USA) (US) Kaiser Permanente United States (USA) (US) Institute of Biological Psychiatry Denmark (DK) Leiden University Medical Center Netherlands (NL)

How to cite

APA:

Andlauer, T.F., Guzman-Parra, J., González, M.J., Gil Flores, S., Cabaleiro Fabeiro, F.J., del Río Noriega, F.,... Müller-Myhsok, B. (2021). Bipolar multiplex families have an increased burden of common risk variants for psychiatric disorders. Molecular Psychiatry, 26(4), 1286-1298. https://doi.org/10.1038/s41380-019-0558-2

MLA:

Andlauer, Till F.M., et al. "Bipolar multiplex families have an increased burden of common risk variants for psychiatric disorders." Molecular Psychiatry 26.4 (2021): 1286-1298.

BibTeX: Download