Analysis of shared heritability in common disorders of the brain

2018 Jun 22;360(6395):eaap8757. doi: 10.1126/science.aap8757.

Analysis of shared heritability in common disorders of the brain

Brainstorm ConsortiumVerneri Anttila 1 2 3Brendan Bulik-Sullivan 4 3Hilary K Finucane 2 3 5 6Raymond K Walters 4 2 3Jose Bras 7 8Laramie Duncan 4 2 3 9Valentina Escott-Price 10 11Guido J Falcone 12 13 14Padhraig Gormley 4 2 3 12Rainer Malik 15Nikolaos A Patsopoulos 3 16Stephan Ripke 4 2 3 17Zhi Wei 18Dongmei Yu 2 12Phil H Lee 2 12Patrick Turley 4 3Benjamin Grenier-Boley 19 20 21Vincent Chouraki 19 20 21 22Yoichiro Kamatani 23 24Claudine Berr 25 26 27Luc Letenneur 28 29Didier Hannequin 30 31Philippe Amouyel 19 20 21 22Anne Boland 32Jean-François Deleuze 32Emmanuelle Duron 33 34Badri N Vardarajan 35Christiane Reitz 36Alison M Goate 37Matthew J Huentelman 38M Ilyas Kamboh 39Eric B Larson 40 41Ekaterina Rogaeva 42Peter St George-Hyslop 42 43Hakon Hakonarson 44 45 46Walter A Kukull 47Lindsay A Farrer 48Lisa L Barnes 49 50 51Thomas G Beach 52F Yesim Demirci 39Elizabeth Head 53Christine M Hulette 54Gregory A Jicha 55John S K Kauwe 56Jeffrey A Kaye 57James B Leverenz 58Allan I Levey 59Andrew P Lieberman 60Vernon S Pankratz 61Wayne W Poon 62Joseph F Quinn 63 64Andrew J Saykin 65Lon S Schneider 66Amanda G Smith 67Joshua A Sonnen 68 69Robert A Stern 70Vivianna M Van Deerlin 71Linda J Van Eldik 53Denise Harold 72Giancarlo Russo 73David C Rubinsztein 74 75Anthony Bayer 76Magda Tsolaki 77 78Petra Proitsi 79Nick C Fox 80 7Harald Hampel 81 82 83 84Michael J Owen 85 86Simon Mead 87Peter Passmore 88Kevin Morgan 89Markus M Nöthen 90 91Martin Rossor 92Michelle K Lupton 93 94Per Hoffmann 90 91 95 96Johannes Kornhuber 97Brian Lawlor 98Andrew McQuillin 99Ammar Al-Chalabi 100 101Joshua C Bis 102Agustin Ruiz 103 104Mercè Boada 103Sudha Seshadri 105 106 107Alexa Beiser 108 109 107Kenneth Rice 110Sven J van der Lee 111Philip L De Jager 112Daniel H Geschwind 113 114 115Matthias Riemenschneider 116Steffi Riedel-Heller 117Jerome I Rotter 118Gerhard Ransmayr 119Bradley T Hyman 13 14Carlos Cruchaga 120Montserrat Alegret 103Bendik Winsvold 121 122Priit Palta 123 124Kai-How Farh 125 3Ester Cuenca-Leon 12 3 2Nicholas Furlotte 126Tobias Kurth 127Lannie Ligthart 128Gisela M Terwindt 129Tobias Freilinger 130 131Caroline Ran 132Scott D Gordon 93Guntram Borck 133Hieab H H Adams 111 134Terho Lehtimäki 135Juho Wedenoja 136 137Julie E Buring 138Markus Schürks 139Maria Hrafnsdottir 140Jouke-Jan Hottenga 128 141Brenda Penninx 142Ville Artto 143Mari Kaunisto 123Salli Vepsäläinen 143Nicholas G Martin 93Grant W Montgomery 93 144Mitja I Kurki 4 3 12 123Eija Hämäläinen 123Hailiang Huang 4 2 145Jie Huang 146 147Cynthia Sandor 148Caleb Webber 148 11Bertram Muller-Myhsok 149 150 151Stefan Schreiber 152 153Veikko Salomaa 154Elizabeth Loehrer 155Hartmut Göbel 156Alfons Macaya 157Patricia Pozo-Rosich 158 159Thomas Hansen 160 161Thomas Werge 161 162 163Jaakko Kaprio 123 137Andres Metspalu 124Christian Kubisch 164Michel D Ferrari 129Andrea C Belin 132Arn M J M van den Maagdenberg 165 129John-Anker Zwart 166Dorret Boomsma 167 128Nicholas Eriksson 126Jes Olesen 160Daniel I Chasman 168 14Dale R Nyholt 169Andreja Avbersek 170Larry Baum 171Samuel Berkovic 172Jonathan Bradfield 173Russell J Buono 174 175 176Claudia B Catarino 170 177Patrick Cossette 178Peter De Jonghe 179 180 181Chantal Depondt 182Dennis Dlugos 183 184Thomas N Ferraro 185 186Jacqueline French 187Helle Hjalgrim 188Jennifer Jamnadas-Khoda 170 189Reetta Kälviäinen 190 191Wolfram S Kunz 192 193Holger Lerche 131Costin Leu 194Dick Lindhout 195 196Warren Lo 197 198Daniel Lowenstein 199Mark McCormack 200 201Rikke S Møller 202 203Anne Molloy 204Ping-Wing Ng 205 206Karen Oliver 207Michael Privitera 208 209Rodney Radtke 210Ann-Kathrin Ruppert 211Thomas Sander 211Steven Schachter 212 13 14Christoph Schankin 213 214Ingrid Scheffer 215 216 217Susanne Schoch 218Sanjay M Sisodiya 219 220Philip Smith 221Michael Sperling 222Pasquale Striano 223Rainer Surges 224 225G Neil Thomas 226Frank Visscher 227Christopher D Whelan 200Federico Zara 228Erin L Heinzen 229Anthony Marson 230 231Felicitas Becker 232 233Hans Stroink 234Fritz Zimprich 235Thomas Gasser 236 237Raphael Gibbs 238Peter Heutink 237 236Maria Martinez 239 240Huw R Morris 219Manu Sharma 241Mina Ryten 219Kin Y Mok 8 242Sara Pulit 243 244 3Steve Bevan 245Elizabeth Holliday 246John Attia 247 248Thomas Battey 12 249Giorgio Boncoraglio 250 251Vincent Thijs 217 252Wei-Min Chen 253Braxton Mitchell 254 255Peter Rothwell 256Pankaj Sharma 257 258Cathie Sudlow 259Astrid Vicente 260 261Hugh Markus 262Christina Kourkoulis 3 263 12Joana Pera 264Miriam Raffeld 3 12 263 265Scott Silliman 266Vesna Boraska Perica 267Laura M Thornton 268Laura M Huckins 269N William Rayner 270 271 272Cathryn M Lewis 273Monica Gratacos 274Filip Rybakowski 275Anna Keski-Rahkonen 276Anu Raevuori 277 276James I Hudson 278Ted Reichborn-Kjennerud 279 280Palmiero Monteleone 281Andreas Karwautz 282Katrin Mannik 124 283Jessica H Baker 268Julie K O’Toole 284Sara E Trace 285Oliver S P Davis 286Sietske G Helder 287 273Stefan Ehrlich 288Beate Herpertz-Dahlmann 289Unna N Danner 290 291Annemarie A van Elburg 290 291Maurizio Clementi 292Monica Forzan 293Elisa Docampo 294 295Jolanta Lissowska 296Joanna Hauser 297Alfonso Tortorella 298Mario Maj 299Fragiskos Gonidakis 300Konstantinos Tziouvas 301Hana Papezova 302 303Zeynep Yilmaz 268Gudrun Wagner 304Sarah Cohen-Woods 305Stefan Herms 90 91 95 96Antonio Julià 306Raquel Rabionet 307 308 309 310Danielle M Dick 311Samuli Ripatti 123 137 312Ole A Andreassen 313 314Thomas Espeseth 313 315 316Astri J Lundervold 317 316Vidar M Steen 318 319Dalila Pinto 320 321 322 323Stephen W Scherer 324 325Harald Aschauer 326Alexandra Schosser 327 328Lars Alfredsson 329Leonid Padyukov 330Katherine A Halmi 331James Mitchell 332 333Michael Strober 334Andrew W Bergen 335 336Walter Kaye 337Jin Peng Szatkiewicz 268Bru Cormand 307 308 309 338Josep Antoni Ramos-Quiroga 339 340 341 342Cristina Sánchez-Mora 340 339 341Marta Ribasés 340 339 341Miguel Casas 343 344 339 345Amaia Hervas 346Maria Jesús Arranz 347Jan Haavik 348 349Tetyana Zayats 348 4Stefan Johansson 350 319Nigel Williams 10Astrid Dempfle 351Aribert Rothenberger 352Jonna Kuntsi 353Robert D Oades 354Tobias Banaschewski 355Barbara Franke 356 357 358Jan K Buitelaar 359 360Alejandro Arias Vasquez 361Alysa E Doyle 263 14Andreas Reif 362Klaus-Peter Lesch 363 364 365Christine Freitag 366Olga Rivero 365Haukur Palmason 140Marcel Romanos 367Kate Langley 368 85Marcella Rietschel 369Stephanie H Witt 369Soeren Dalsgaard 370 163 371Anders D Børglum 372 163 373 374Irwin Waldman 375Beth Wilmot 376Nikolas Molly 377Claiton H D Bau 378 379Jennifer Crosbie 380 381Russell Schachar 382 381Sandra K Loo 383James J McGough 384Eugenio H Grevet 379 385Sarah E Medland 93Elise Robinson 4 2 6Lauren A Weiss 386 387 388Elena Bacchelli 389Anthony Bailey 390 391Vanessa Bal 386 387 388Agatino Battaglia 392Catalina Betancur 393Patrick Bolton 353 394Rita Cantor 395Patrícia Celestino-Soper 396Geraldine Dawson 397Silvia De Rubeis 320 321 398Frederico Duque 399 400Andrew Green 401 402Sabine M Klauck 403Marion Leboyer 404 405 406Pat Levitt 407 66Elena Maestrini 389Shrikant Mane 408 409Daniel Moreno- De-Luca 410Jeremy Parr 411 412 413Regina Regan 402 414Abraham Reichenberg 269Sven Sandin 320 321 415Jacob Vorstman 416 417Thomas Wassink 418Ellen Wijsman 419 110Edwin Cook 420Susan Santangelo 421 422Richard Delorme 423 424Bernadette Rogé 425 426 427Tiago Magalhaes 414 428Dan Arking 429Thomas G Schulze 430 431 369 432 433Robert C Thompson 434 435Jana Strohmaier 369 436Keith Matthews 437 438Ingrid Melle 439 440Derek Morris 441Douglas Blackwood 442Andrew McIntosh 442Sarah E Bergen 415Martin Schalling 443 444Stéphane Jamain 404 405 406Anna Maaser 91 90Sascha B Fischer 95 445Céline S Reinbold 95 445Janice M Fullerton 446 447José Guzman-Parra 448 449Fermin Mayoral 448 449Peter R Schofield 446 447Sven Cichon 95 445 450Thomas W Mühleisen 450 445Franziska Degenhardt 451Johannes Schumacher 451Michael Bauer 452Philip B Mitchell 453 454Elliot S Gershon 455John Rice 456James B Potash 432Peter P Zandi 457Nick Craddock 85I Nicol Ferrier 411Martin Alda 458 459Guy A Rouleau 460 461Gustavo Turecki 462Roel Ophoff 463 464Carlos Pato 465Adebayo Anjorin 466Eli Stahl 269 312Markus Leber 467Piotr M Czerski 468Cristiana Cruceanu 469 470Ian R Jones 471Danielle Posthuma 472 473Till F M Andlauer 149 474Andreas J Forstner 91 90 96 95 475Fabian Streit 369Bernhard T Baune 476Tracy Air 476Grant Sinnamon 477 478Naomi R Wray 144 479Donald J MacIntyre 480David Porteous 481Georg Homuth 482Margarita Rivera 483 273Jakob Grove 163 373 372 484Christel M Middeldorp 485 486 128Ian Hickie 487Michele Pergadia 120Divya Mehta 488 489Johannes H Smit 142 490 491Rick Jansen 142Eco de Geus 128 490Erin Dunn 12 492Qingqin S Li 493Matthias Nauck 494 495Robert A Schoevers 496Aartjan Tf Beekman 142 497James A Knowles 498Alexander Viktorin 415Paul Arnold 499 500 417Cathy L Barr 501 382 381Gabriel Bedoya-Berrio 502O Joseph Bienvenu 503Helena Brentani 504Christie Burton 382Beatriz Camarena 505Carolina Cappi 504Danielle Cath 506 507Maria Cavallini 508Daniele Cusi 509Sabrina Darrow 510Damiaan Denys 511 512Eske M Derks 93Andrea Dietrich 513 514Thomas Fernandez 515Martijn Figee 511 320Nelson Freimer 463Gloria Gerber 12Marco Grados 432Erica Greenberg 263Gregory L Hanna 435Andreas Hartmann 516 517 518Matthew E Hirschtritt 386 388Pieter J Hoekstra 514Alden Huang 519 384Chaim Huyser 520 521Cornelia Illmann 263Michael Jenike 14Samuel Kuperman 522Bennett Leventhal 510Christine Lochner 523Gholson J Lyon 524Fabio Macciardi 525Marcos Madruga-Garrido 526Irene A Malaty 527Athanasios Maras 528Lauren McGrath 529Eurípedes C Miguel 530Pablo Mir 531 532Gerald Nestadt 432Humberto Nicolini 533 534Michael S Okun 535 536 537Andrew Pakstis 409Peristera Paschou 538John Piacentini 384Christopher Pittenger 539Kerstin Plessen 540 541Vasily Ramensky 542Eliana M Ramos 543Victor Reus 386 388Margaret A Richter 544 545Mark A Riddle 503Mary M Robertson 546Veit Roessner 547Maria Rosário 548 549Jack F Samuels 432Paul Sandor 545 550 551Dan J Stein 552 523Fotis Tsetsos 553Filip Van Nieuwerburgh 554Sarah Weatherall 12Jens R Wendland 555Tomasz Wolanczyk 556Yulia Worbe 557 558 559Gwyneth Zai 545Fernando S Goes 432Nicole McLaughlin 560 561Paul S Nestadt 432Hans-Jorgen Grabe 562Christel Depienne 563 564 565Anuar Konkashbaev 566Nuria Lanzagorta 534Ana Valencia-Duarte 567 568Elvira Bramon 99Nancy Buccola 569Wiepke Cahn 570Murray Cairns 571 572 573Siow A Chong 574David Cohen 575 576Benedicto Crespo-Facorro 577 341James Crowley 285Michael Davidson 578 579Lynn DeLisi 580 14Timothy Dinan 581 582Gary Donohoe 583Elodie Drapeau 269 320 321Jubao Duan 584 585Lieuwe Haan 511 586David Hougaard 587Sena Karachanak-Yankova 588Andrey Khrunin 589Janis Klovins 590Vaidutis Kučinskas 591Jimmy Lee Chee Keong 592Svetlana Limborska 593Carmel Loughland 594 247Jouko Lönnqvist 154 595Brion Maher 457Manuel Mattheisen 596 597 598Colm McDonald 599 600Kieran C Murphy 601Igor Nenadic 602 603Jim van Os 570 604 605Christos Pantelis 606 607 217Michele Pato 465Tracey Petryshen 2 12Digby Quested 608 609Panos Roussos 269Alan R Sanders 610 585Ulrich Schall 247Sibylle G Schwab 611Kang Sim 612 613 574Hon-Cheong So 614 615 616Elisabeth Stögmann 235Mythily Subramaniam 574 613Draga Toncheva 588John Waddington 200James Walters 85 86Mark Weiser 579 617Wei Cheng 268Robert Cloninger 618David Curtis 619 620Pablo V Gejman 585 610Frans Henskens 621 622 248Morten Mattingsdal 439 623Sang-Yun Oh 624 625Rodney Scott 247 248 626Bradley Webb 627Gerome Breen 628 629Claire Churchhouse 4 2 3Cynthia M Bulik 630 415Mark Daly 4 2 3Martin Dichgans 15 150Stephen V Faraone 631Rita Guerreiro 7 8Peter Holmans 10Kenneth S Kendler 632Bobby Koeleman 633Carol A Mathews 634 537Alkes Price 3 6Jeremiah Scharf 2 3 12 12 635 13 14Pamela Sklar 269Julie Williams 10 11Nicholas W Wood 8 619Chris Cotsapas 3 636Aarno Palotie 4 2 3 12 13 14 123Jordan W Smoller 2 12Patrick Sullivan 630 637Jonathan Rosand 3 12 13 14Aiden Corvin 638 639Benjamin M Neale 1 2 3Jonathan M Schott 80Richard Anney 85 86Josephine Elia 640 641Maria Grigoroiu-Serbanescu 642Howard J Edenberg 643Robin Murray 353Affiliations expand

Free PMC article

Abstract

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

INTRODUCTION

Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders.

RATIONALE

Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities’ assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms.

RESULTS

Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer’s disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations.

CONCLUSION

The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important “scaffolding” to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders.

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About S. R. Zelenz 102 Articles
S.R. Zelenz has worked in education for 20 years. Working with students from all walks of life, cultures, races, and social diversity, Zelenz’s research in Educational Leadership led to finding a better way to approach learning for students with trauma histories. Many were juvenile offenders, gang members, diagnosed with varying behavioral disorders, or had family histories of violence, murder, or narcissistic parenting. This research could not be effectively accomplished without further understanding: how epigenetic trauma inheritance may be impacting these students; how brain development from trauma may be impacting their behavioral and emotional development; as well as deep understanding of psychology and its varying classifications for behavioral and personality disorders. The goal is to find solutions for changing the conversation and making a real difference for these students. She has also worked with nonprofits of varying focus areas for the last 25 years. Her undergraduate degree in Arts Administration and Music prepared her for managing nonprofits of any size as well as procuring funding so that they can achieve their goals. Pairing her nonprofit background with her education background, she has been able to make a difference for over 200 nonprofits worldwide, written curriculum for schools across the globe, and assisted many arts organizations through performance and management.