Immune, Developmental, and Synaptic Pathways Define Bipolar Disorder Clinical Heterogeneity.
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van der Veen Tracey, Tesfaye Markos, Yang Jessica Mei Kay, Boltz Toni, David Friederike S, Crinion Shane, Koromina Maria, Andlauer Till F M, Bigdeli Tim B, Coombes Brandon J, Greenwood Tiffany A, Panagiotaropoulou Georgia, Parker Nadine, Sung Heejong, Bass Nicholas, Coleman Jonathan R I, Guzman-Parra José, Kalman Janos L, McGrouther Caroline C, Mitchell Brittany L, Rangan Aaditya V, Scott Katie, Shadrin Alexey, Smith Daniel J, Vreeker Annabel, Adorjan Kristina, Albani Diego, Alemany Silvia, Alliey-Rodriguez Ney, Antoniou Anastasia, Bauer Michael, Beins Eva C, Boks Marco P, Bosch Rosa, Brumpton Ben M, Brunkhorst-Kanaan Nathalie, Budde Monika, Byerley William, Cabana-Domínguez Judit, Cairns Murray J, Carpiniello Bernardo, Casas Miquel, Cervantes Pablo, Chatzinakos Chris, Clarke Toni-Kim, Claus Isabelle, Cruceanu Cristiana, Cuellar-Barboza Alfredo, Czerski Piotr M, Dafnas Konstantinos, Dale Anders M, Dalkner Nina, DePaulo J Raymond, Degenhardt Franziska, Djurovic Srdjan, Escott-Price Valentina, Fanous Ayman H, Fellendorf Frederike T, Ferrier I Nicol, Forty Liz, Frank Josef, Frei Oleksandr, Freimer Nelson B, Garnham Julie, Gizer Ian R, Gordon Scott D, Gordon-Smith Katherine, Hahn Tim, Marian L, Harder Arvid, Hautzinger Martin, Heilbronner Urs, Hellgren Dennis, Herms Stefan, Hickie Ian B, Hoffmann Per, Holmans Peter A, Jamain Stéphane, Jonsson Lina, Kennedy James L, Kittel-Schneider Sarah, Knowles James A, Koch Elise, Kogevinas Manolis, Kranz Thorsten M, Kushner Steven A, Lavebratt Catharina, Lawrence Jacob, Leber Markus, Lind Penelope A, Lucae Susanne, Lundberg Martin, MacIntyre Donald J, Maier Wolfgang, Maihofer Adam X, Malaspina Dolores, Manchia Mirko, Maratou Eirini, Martinsson Lina, McInnis Melvin G, McKay James D, Medeiros Helena, Meyer-Lindenberg Andreas, Millischer Vincent, Morris Derek W, Moutsatsou Paraskevi, Mühleisen Thomas W, 'Donovan Claire O, Olsen Catherine M, Papiol Sergi, Pardiñas Antonio F, Perry Amy, Pfennig Andrea, Pisanu Claudia, Potash James B, Quested Digby, Rapaport Mark H, Regeer Eline J, Rice John P, Rivera Margarita, Schulte Eva C, Senner Fanny, Shilling Paul D, Sindermann Lisa, Sirignano Lea, Siskind Dan, Slaney Claire, Smeland Olav B, Sobell Janet L, Artigas Maria Soler, Stein Dan J, Stein Frederike, Swiatkowska Beata, Thorp Jackson G, Toma Claudio, Tondo Leonardo, Tooney Paul A, Vawter Marquis P, Vedder Helmut, Walters James T R, Witt Stephanie H, Young Allan H, Zandi Peter P, Zillich Lea, Estonian Biobank research team, Genomic Psychiatry Cohort (GPC) Investigators, HUNT All-In Psychiatry, Adolfsson Rolf, Alfredsson Lars, Backlund Lena, Baune Bernhard T, Bellivier Frank, Bengesser Susanne, Berrettini Wade H, Biernacka Joanna M, Blackwood Douglas, Boehnke Michael, Breen Gerome, Carr Vaughan J, Catts Stanley, Cichon Sven, Corvin Aiden, Craddock Nicholas, Dannlowski Udo, Dikeos Dimitris, Esko Tõnu, Etain Bruno, Ferentinos Panagiotis, Frye Mark, Fullerton Janice M, Gawlik Micha, Gershon Elliot S, Goes Fernando S, Green Melissa J, Hauser Joanna, Henskens Frans A, Hjerling-Leffler Jens, Jones Ian, Jones Lisa A, Kahn René S, Kelsoe John R, Kircher Tilo, Kirov George, Kobayashi Nene, Landén Mikael, Leboyer Marion, Lenger Melanie, Li Qingqin S, Lissowska Jolanta, Loughland Carmel, Luykx Jurjen J, Martin Nicholas G, Mathews Carol A, Mayoral Fermin, McElroy Susan L, McIntosh Andrew M, Medland Sarah E, Melle Ingrid, Mitchell Philip B, Morken Gunnar, Myers Richard M, Möser Chiara, Müller-Myhsok Bertram, Neale Benjamin M, Nievergelt Caroline M, Nurnberger John I, Nöthen Markus M, O'Donovan Michael C, Oedegaard Ketil J, Olsson Tomas, Owen Michael J, Paciga Sara A, Pantelis Christos, Pato Carlos N, Pato Michele T, Patrinos George P, Pawlak Joanna M, Perlis Roy, Ramos-Quiroga Josep Antoni, Reif Andreas, Reininghaus Eva Z, Ribasés Marta, Rietschel Marcella, Ripke Stephan, Rouleau Guy A, Schall Ulrich, Schalling Martin, Schofield Peter R, Schulze Thomas G, Scott Laura J, Scott Rodney J, Serretti Alessandro, Smoller Jordan W, Squassina Alessio, Stahl Eli A, Stordal Eystein, Streit Fabian, Sullivan Patrick F, Turecki Gustavo, Vaaler Arne E, Vieta Eduard, Vincent John B, Waldman Irwin D, Weickert Cynthia S, Weickert Thomas W, Whiteman David C, Alda Martin, Ophoff Roel A, O'Connell Kevin S, Mullins Niamh, Forstner Andreas J, Grigoroiu-Serbanescu Maria, Edenberg Howard J, McMahon Francis J, Andreassen Ole A, Di Florio Arianna, McQuillin Andrew, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium
Аннотация
OBJECTIVE: To test the hypothesis that clinically distinct subphenotypes of BD are associated with different underlying common variant genetic architectures.
DESIGN SETTING AND PARTICIPANTS: This multicenter study included a primary genome-wide association study (GWAS) of up to 23,819 bipolar disorder (BD) cases and 163,839 controls. These results were integrated via multi-trait analysis of GWAS (MTAG) with external summary statistics for BD (59,287 cases; 781,022 controls) and schizophrenia (SCZ; 53,386 cases; 77,258 controls). Sample overlap was statistically accounted for.
MAIN OUTCOMES AND MEASURES: The primary outcomes were the genetic dimensions underlying BD heterogeneity, differentiated by single nucleotide polymorphism (SNP)-heritability (h 2 SNP ), genetic correlations, genomic loci ( P ≤5×10 -8 ), and functional, cell-type, and gene-expression pathway analyses.
RESULTS: We identified four genetically-informed dimensions of BD: Severe Illness, Core Mania, Externalizing/Impulsive Comorbidity, and Internalizing/Affective Comorbidity. The analyses yielded up to 181 subphenotype-associated loci, 53 of which are novel. The Severe Illness Dimension was characterized by a unique neuro-immune signature (a protective association with HLA-DMB , P =2.50×10 -273 ) evident only when leveraging SCZ genetic data. The Internalizing/Affective dimension was associated with neurodevelopmental genes (e.g., DCC ). Notably, the rapid-cycling subphenotype showed a unique signature of strong negative selection, a finding not observed in other subphenotypes.
CONCLUSIONS AND RELEVANCE: The clinical heterogeneity of bipolar disorder appears to be defined by a complex and multi-layered genetic architecture. The presented findings provide an empirical framework that may advance psychiatric nosology beyond its current diagnostic boundaries. These results may also inform future research to identify targets for personalized interventions. The delineation of these genetically-informed dimensions offers specific, biologically-grounded hypotheses for subsequent therapeutic discovery. Establishing such a framework is an essential step toward refining diagnostic criteria and developing more effective, personalized treatments. This work lays the foundation for a transition from a uniform treatment model to the paradigm of precision psychiatry.
KEY POINTS: Question: What are the distinct genetic architectures underlying the clinical heterogeneity of bipolar disorder?Findings: In this genetic study of 23,819 bipolar disorder (BD) cases and 163,839 controls, clinical heterogeneity mapped onto four genetically-informed dimensions. A severe illness dimension was defined by a neuro-immune signature ( HLA-DMB ) shared with schizophrenia. An affective comorbidity dimension was distinguished by neurodevelopmental pathways involving axonal guidance ( DCC ). Notably, the rapid-cycling phenotype showed evidence of purifying selection, suggesting influence by rare, highly penetrant alleles. Meaning: These findings provide a data-driven biological framework for bipolar disorder, guiding future research toward patient stratification and targeted therapeutics.