Scholarlink

<p>Psychiatric disorders display high levels of comorbidity and genetic overlap<sup><CitationRef CitationID="CR1">1</CitationRef>,<CitationRef CitationID="CR2">2</CitationRef></sup>, challenging current diagnostic boundaries. For disorders for which diagnostic separation has been most debated, such as schizophrenia and bipolar disorder<sup><CitationRef CitationID="CR3">3</CitationRef></sup>, genomic methods have revealed that the majority of genetic signal is shared<sup><CitationRef CitationID="CR4">4</CitationRef></sup>. While over a hundred pleiotropic loci have been identified by recent cross-disorder analyses<sup><CitationRef CitationID="CR5">5</CitationRef></sup>, the full scope of shared and disorder-specific genetic influences remains poorly defined. Here we addressed this gap by triangulating across a suite of cutting-edge statistical and functional genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders (1,056,201 cases). Using genetic association data from common variants, we identified and characterized five underlying genomic factors that explained the majority of the genetic variance of the individual disorders (around 66% on average) and were associated with 238 pleiotropic loci. The two factors defined by (1) Schizophrenia and bipolar disorders (SB factor); and (2) major depression, PTSD and anxiety (Internalizing factor) showed high levels of polygenic overlap<sup><CitationRef CitationID="CR6">6</CitationRef></sup> and local genetic correlation and very few disorder-specific loci. The genetic signal shared across all 14 disorders was enriched for broad biological processes (for example, transcriptional regulation), while more specific pathways were shared at the level of the individual factors. The shared genetic signal across the SB factor was substantially enriched in genes expressed in excitatory neurons, whereas the Internalizing factor was associated with oligodendrocyte biology. These observations may inform a more neurobiologically valid psychiatric nosology and implicate targets for therapeutic development designed to treat commonly occurring comorbid presentations.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Mapping the genetic landscape across 14 psychiatric disorders

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月10日

查看全文
  • Andrew D. Grotzinger,
  • Josefin Werme,
  • Wouter J. Peyrot,
  • Oleksandr Frei,
  • Christiaan de Leeuw,
  • Lucy K. Bicks,
  • Qiuyu Guo,
  • Michael P. Margolis,
  • Brandon J. Coombes,
  • Anthony Batzler,
  • Vanessa Pazdernik,
  • Joanna M. Biernacka,
  • Ole A. Andreassen,
  • Verneri Anttila,
  • Anders D. Børglum,
  • Gerome Breen,
  • Na Cai,
  • Ditte Demontis,
  • Howard J. Edenberg,
  • Stephen V. Faraone,
  • Barbara Franke,
  • Michael J. Gandal,
  • Joel Gelernter,
  • Alexander S. Hatoum,
  • John M. Hettema,
  • Emma C. Johnson,
  • Katherine G. Jonas,
  • James A. Knowles,
  • Karestan C. Koenen,
  • Adam X. Maihofer,
  • Travis T. Mallard,
  • Manuel Mattheisen,
  • Karen S. Mitchell,
  • Benjamin M. Neale,
  • Caroline M. Nievergelt,
  • John I. Nurnberger,
  • Kevin S. O’Connell,
  • Roseann E. Peterson,
  • Elise B. Robinson,
  • Sandra S. Sanchez-Roige,
  • Susan L. Santangelo,
  • Jeremiah M. Scharf,
  • Hreinn Stefansson,
  • Kari Stefansson,
  • Murray B. Stein,
  • Nora I. Strom,
  • Laura M. Thornton,
  • Elliot M. Tucker-Drob,
  • Brad Verhulst,
  • Irwin D. Waldman,
  • G. Bragi Walters,
  • Naomi R. Wray,
  • Dongmei Yu,
  • Daniel E. Adkins,
  • Georg W. Alpers,
  • Helga Ask,
  • Sintia I. Belangero,
  • Ottar Bjerkeset,
  • Sigrid Børte,
  • Sandra A. Brown,
  • Enrique Castelao,
  • Hilary Coon,
  • William E. Copeland,
  • Elizabeth C. Corfield,
  • Darina Czamara,
  • Jürgen Deckert,
  • Anna R. Docherty,
  • Katharina Domschke,
  • Ole Kristian Drange,
  • Thalia C. Eley,
  • Angelika Erhardt-Lehmann,
  • Andreas J. Forstner,
  • Miguel Garcia-Argibay,
  • Scott D. Gordon,
  • Ian B. Hickie,
  • Iiris Hovatta,
  • Matthew H. Iveson,
  • James L. Kennedy,
  • Henrik Larsson,
  • Daniel F. Levey,
  • Christine Lochner,
  • Michelle K. Lupton,
  • Hermine HM Maes,
  • Eduard Maron,
  • Nicholas G. Martin,
  • Sandra M. Meier,
  • Christiane A. Melzig,
  • Brittany L. Mitchell,
  • Teemu Palviainen,
  • Giorgio Pistis,
  • Martin Preisig,
  • Börge Schmidt,
  • Johannes Schumacher,
  • Andrey A. Shabalin,
  • Anne Heidi Skogholt,
  • Dan J. Stein,
  • Eystein Stordal,
  • Andreas Ströhle,
  • Elisa Tasanko,
  • Laurent Thomas,
  • Henning Tiemeier,
  • Heike Weber,
  • Bendik S. Winsvold,
  • Clement C. Zai,
  • Gwyneth Zai,
  • John-Anker Zwart,
  • Silvia Alemany,
  • Claiton HD Bau,
  • Dorret I. Boomsma,
  • Rosa Bosch,
  • Isabell Brikell,
  • Christie L. Burton,
  • Miquel Casas,
  • Bru Cormand,
  • Jennifer Crosbie,
  • Alysa E. Doyle,
  • Josephine Elia,
  • Joseph T. Glessner,
  • Eugenio H. Grevet,
  • Jan Haavik,
  • Alexandra Havdahl,
  • Ziarih Hawi,
  • Anke Hinney,
  • Daniel P. Howrigan,
  • Marieke Klein,
  • Henry R. Kranzler,
  • Jonna Kuntsi,
  • Kate Langley,
  • Klaus-Peter Lesch,
  • Calwing Liao,
  • Sandra K. Loo,
  • James J. McGough,
  • Sarah E. Medland,
  • Nina R. Mota,
  • Michael C. O’Donovan,
  • Danielle Posthuma,
  • Josep Antoni Ramos-Quiroga,
  • Andreas Reif,
  • Marta Ribasés,
  • Diego L. Rovaris,
  • Russell J. Schachar,
  • Stephen W. Scherer,
  • Yingjie Shi,
  • María Soler Artigas,
  • Edmund JS Sonuga-Barke,
  • Hans-Christoph Steinhausen,
  • Ludger Tebartz van Elst,
  • Martin Tesli,
  • Raymond K. Walters,
  • Stephanie H. Witt,
  • Yanli Zhang-James,
  • Edwin H. Cook,
  • Jakob Grove,
  • Susan S. Kuo,
  • Joseph Piven,
  • Stephan J. Sanders,
  • Mohammed Uddin,
  • Jacob AS Vorstman,
  • Varun Warrier,
  • Lauren A. Weiss,
  • Martin Alda,
  • Lars Alfredsson,
  • Till F. M. Andlauer,
  • Nicholas Bass,
  • Anthony J. Batzler,
  • Bernhard T. Baune,
  • Eva C. Beins,
  • Tim B. Bigdeli,
  • Sven Cichon,
  • Jonathan RI Coleman,
  • Alfredo B. Cuellar-Barboza,
  • Udo Dannlowski,
  • Friederike S. David,
  • Josef Frank,
  • Janice M. Fullerton,
  • Fernando S. Goes,
  • Maria Grigoroiu-Serbanescu,
  • Per Hoffmann,
  • Janos L. Kalman,
  • Kristi Krebs,
  • Mikael Landén,
  • Cathryn M. Lewis,
  • Qingqin S. Li,
  • Penelope A. Lind,
  • Jurjen J. Luykx,
  • Mirko Manchia,
  • Morten Mattingsdal,
  • Andrew M. McIntosh,
  • Andrew McQuillin,
  • Anna Meloni,
  • Lili Milani,
  • Philip B. Mitchell,
  • Derek W. Morris,
  • Niamh Mullins,
  • Woojae Myung,
  • John I. Nurnberger Jr,
  • Roel A. Ophoff,
  • Michael J. Owen,
  • George P. Patrinos,
  • Claudia Pisanu,
  • James J. Prisciandaro,
  • Eva Z. Reininghaus,
  • John P. Rice,
  • Marcella Rietschel,
  • Eva C. Schulte,
  • Alessandro Serretti,
  • Lea Sirignano,
  • Alessio Squassina,
  • Fabian Streit,
  • Jana Strohmaier,
  • Tracey van der Veen,
  • Marquis P. Vawter,
  • John B. Vincent,
  • Peter P. Zandi,
  • Lea Zillich,
  • Roger A. Adan,
  • Andreas Birgegård,
  • Cynthia M. Bulik,
  • Christian Dina,
  • Monika Dmitrzak-Weglarz,
  • Elisa Docampo,
  • Karin M. Egberts,
  • Fernando Fernandez-Aranda,
  • Katrin E. Giel,
  • Philip Gorwood,
  • Christopher Hübel,
  • James I. Hudson,
  • Susana Jimenez-Murcia,
  • Jennifer Jordan,
  • Gursharan K. Kalsi,
  • Jaakko Kaprio,
  • Leila Karhunen,
  • Martien J. H. Kas,
  • Martin A. Kennedy,
  • Janne T. Larsen,
  • Lisa R. Lilenfeld,
  • Alessio Maria Monteleone,
  • Melissa A. Munn-Chernoff,
  • Benedetta Nacmias,
  • Liselotte V. Petersen,
  • Dalila Pinto,
  • Anu Raevuori,
  • Nicolas Ramoz,
  • Valdo Ricca,
  • Marion E. Roberts,
  • Filip Rybakowski,
  • Ulrike H. Schmidt,
  • Alexandra Schosser,
  • Sandro Sorbi,
  • Michael A. Strober,
  • Hunna J. Watson,
  • Stephan Zipfel,
  • Mark J. Adams,
  • Michael E. Benros,
  • Rodrigo A. Bressan,
  • Enda M. Byrne,
  • Carolina M. Carvalho,
  • Boris Chaumette,
  • Lucia Colodro-Conde,
  • Eske M. Derks,
  • Erin C. Dunn,
  • Chiara Fabbri,
  • Giuseppe Fanelli,
  • Jerome C. Foo,
  • Ary Gadelha,
  • Zachary F. Gerring,
  • Hans J. Grabe,
  • Andrew C. Heath,
  • Kelli Lehto,
  • Douglas F. Levinson,
  • Glyn Lewis,
  • Vanessa K. Ota,
  • Pedro M. Pan,
  • Peristera Paschou,
  • James B. Potash,
  • Brien P. Riley,
  • Giovanni A. Salum,
  • Marcos L. Santoro,
  • Jackson G. Thorp,
  • Sandra Van der Auwera,
  • Bradley T. Webb,
  • Timothy B. Baker,
  • Danielle M. Dick,
  • Dmitriy Drichel,
  • Lindsay A. Farrer,
  • Nathan C. Gaddis,
  • Dana B. Hancock,
  • John E. Hokanson,
  • Jouke-Jan Hottenga,
  • Eric O. Johnson,
  • Pamela A. Madden,
  • Mary L. Marazita,
  • Jesse A. Marks,
  • Daniel W. McNeil,
  • Michael Nothnagel,
  • Bryan C. Quach,
  • Nancy L. Saccone,
  • Nancy YA Sey,
  • Richard Sherva,
  • Scott Vrieze,
  • Alex Waldrop,
  • Georg Winterer,
  • Kendra Young,
  • Stephanie Zellers,
  • Cathy L. Barr,
  • Csaba Barta,
  • Katharina Bey,
  • Oscar J. Bienvenu,
  • Julia Boberg,
  • Jonas Bybjerg-Grauholm,
  • Adrian Camarena,
  • Beatriz Camarena,
  • Danielle C. Cath,
  • James J. Crowley,
  • Andrea Dietrich,
  • Peter Falkai,
  • Thomas V. Fernandez,
  • Daniel A. Geller,
  • Marco A. Grados,
  • Erica L. Greenberg,
  • Edna Grünblatt,
  • Kristen Hagen,
  • Gregory L. Hanna,
  • Bjarne Hansen,
  • Gary A. Heiman,
  • Pieter J. Hoekstra,
  • David M. Hougaard,
  • Norbert Kathmann,
  • Julia Klawohn,
  • Gerd Kvale,
  • Nuria Lanzagorta,
  • Stephanie Le Hellard,
  • Fabio Macciardi,
  • Brion S. Maher,
  • Irene A. Malaty,
  • David Mataix-Cols,
  • Carol A. Mathews,
  • Nicole CR McLaughlin,
  • Euripedes C. Miguel,
  • Kirsten R. Müller-Vahl,
  • Humberto Nicolini,
  • Erika L. Nurmi,
  • Michael S. Okun,
  • Raquel Rabionet,
  • Alfredo Ramirez,
  • Renata Rizzo,
  • Cristina Rodriguez-Fontenla,
  • Paul Sandor,
  • Elles de Schipper,
  • Harvey S. Singer,
  • Eric A. Storch,
  • Jeremy Veenstra-VanderWeele,
  • Michael Wagner,
  • Christopher P. Walker,
  • Søren B. Andersen,
  • Laura J. Bierut,
  • Chia-Yen Chen,
  • Nikolaos P. Daskalakis,
  • Seth G. Disner,
  • Anna R. Docherty,
  • Norah C. Feeny,
  • Lana R. Grasser,
  • Magali Haas,
  • Kelly M. Harrington,
  • Victor M. Hesselbrock,
  • Mohammed H. Ibrahim,
  • Seyma Katrinli,
  • Nathan A. Kimbrel,
  • Jessica L. Maples-Keller,
  • Jacquelyn L. Meyers,
  • Janitza L. Montalvo-Ortiz,
  • Charles P. Morris,
  • Robert H. Pietrzak,
  • Renato Polimanti,
  • Richard J. Rosenblum,
  • Barbara O. Rothbaum,
  • Bart PF Rutten,
  • Soraya Seedat,
  • Alicia K. Smith,
  • Ralph E. Tarter,
  • Muhammad Ayub,
  • Dominique Campion,
  • David Cohen,
  • Angel Consoli,
  • Marta Di Forti,
  • Johan G. Eriksson,
  • Olga YU Fedorenko,
  • Robert Freedman,
  • Raul R. Gainetdinov,
  • Marianna Giannitelli,
  • Ina Giegling,
  • Stephen J. Glatt,
  • Stephanie Godard,
  • Olivier Guillin,
  • Annette M. Hartmann,
  • Svetlana A. Ivanova,
  • Alexander O. Kibitov,
  • Bettina Konte,
  • Claudine Laurent-Levinson,
  • Anastasia Levchenko,
  • Robin Murray,
  • Merete Nordentoft,
  • Cristiano Noto,
  • Diego Quattrone,
  • Dan Rujescu,
  • Safaa Saker-Delye,
  • SIbylle G. Schwab,
  • Florence Thibaut,
  • James TR Walters,
  • Thomas Werge,
  • Dieter B. Wildenauer,
  • Arpana Agrawal,
  • David AA Baranger,
  • Jason D. Boardman,
  • Joseph M. Boden,
  • Ryan Bogdan,
  • Karhleen K. Bucholz,
  • Doo-Sup Choi,
  • Sarah MC Colbert,
  • Joseph D. Deak,
  • Nancy Diazgranados,
  • Alexis C. Edwards,
  • Alison M. Goate,
  • David Goldman,
  • Laura M. Hack,
  • Kathleen Mullan Harris,
  • Sarah M. Hartz,
  • Caroline Hayward,
  • John K. Hewitt,
  • Christian J. Hopfer,
  • Victor M. Karpyak,
  • Kenneth S. Krauter,
  • Evgeny M. Krupitsky,
  • Samuel Kuperman,
  • Jari Lahti,
  • Marius Lahti-Pulkkinen,
  • Dongbing Lai,
  • Alex P. Miller,
  • Abraham A. Palmer,
  • Rohn H. Palmer,
  • John F. Pearson,
  • Bernice Porjesz,
  • Ulrich W. Preuss,
  • Daniel M. Rosenblum,
  • Norbert Scherbaum,
  • Michael Vanyukov,
  • Tamara L. Wall,
  • Robbee Wedow,
  • Stanley H. Weiss,
  • Leah Wetherill,
  • Norbert Wodarz,
  • Haitao Zhang,
  • Hongyu Zhao,
  • Hang Zhou,
  • Peter Zill,
  • Phil H. Lee,
  • Kenneth S. Kendler,
  • Jordan W. Smoller

摘要

Psychiatric disorders display high levels of comorbidity and genetic overlap1,2, challenging current diagnostic boundaries. For disorders for which diagnostic separation has been most debated, such as schizophrenia and bipolar disorder3, genomic methods have revealed that the majority of genetic signal is shared4. While over a hundred pleiotropic loci have been identified by recent cross-disorder analyses5, the full scope of shared and disorder-specific genetic influences remains poorly defined. Here we addressed this gap by triangulating across a suite of cutting-edge statistical and functional genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders (1,056,201 cases). Using genetic association data from common variants, we identified and characterized five underlying genomic factors that explained the majority of the genetic variance of the individual disorders (around 66% on average) and were associated with 238 pleiotropic loci. The two factors defined by (1) Schizophrenia and bipolar disorders (SB factor); and (2) major depression, PTSD and anxiety (Internalizing factor) showed high levels of polygenic overlap6 and local genetic correlation and very few disorder-specific loci. The genetic signal shared across all 14 disorders was enriched for broad biological processes (for example, transcriptional regulation), while more specific pathways were shared at the level of the individual factors. The shared genetic signal across the SB factor was substantially enriched in genes expressed in excitatory neurons, whereas the Internalizing factor was associated with oligodendrocyte biology. These observations may inform a more neurobiologically valid psychiatric nosology and implicate targets for therapeutic development designed to treat commonly occurring comorbid presentations.