Медицинская библиотека · Research square · 2026

Genomic dimensions deconstruct the clinical heterogeneity of bipolar disorder.

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, Hamshere 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, O'Donovan Claire, 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

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Аннотация

Bipolar disorder's (BD) clinical heterogeneity has an unresolved genetic basis. We meta-analyzed genome-wide association studies (GWAS) of 16 BD subphenotypes in 226,032 individuals from 57 cohorts (38,022 cases); 10 advanced to multivariate and multi-trait analyses. Four factors (compulsive, psychotic, dysregulated, internalizing) explained 82.8% of shared genetic variance. BD1 and BD2 loaded on distinct factors despite a high genetic correlation; 87.0% of common-factor loci were significant in neither subtype. Unipolar mania aligned with psychosis over internalizing, and was distinguishable from BD1, and rapid cycling showed heritable cross-domain liability. We identified 356 risk loci, 158 novel, including the first univariate-GWAS associations for psychosis, unipolar mania, rapid cycling and schizoaffective disorder-and 249 credible genes (89 high-confidence), 12 with approved-drug or clinical-phase annotations. Cell-type association showed a midbrain dopaminergic-GABAergic gradient along the psychotic factor. BD's genetic architecture appears hierarchical-a general liability resolving into dimensions of course and comorbidity, beyond subtypes.

Для цитирования: 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, Hamshere 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, O'Donovan Claire, 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. Genomic dimensions deconstruct the clinical heterogeneity of bipolar disorder.. Research square. 2026. DOI: 10.21203/rs.3.rs-10041361/v1.

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