2018 Jun 22;360(6395):eaap8757. doi: 10.1126/science.aap8757.
Analysis of shared heritability in common disorders of the brain
Brainstorm Consortium; Verneri Anttila 1 2 3, Brendan Bulik-Sullivan 4 3, Hilary K Finucane 2 3 5 6, Raymond K Walters 4 2 3, Jose Bras 7 8, Laramie Duncan 4 2 3 9, Valentina Escott-Price 10 11, Guido J Falcone 12 13 14, Padhraig Gormley 4 2 3 12, Rainer Malik 15, Nikolaos A Patsopoulos 3 16, Stephan Ripke 4 2 3 17, Zhi Wei 18, Dongmei Yu 2 12, Phil H Lee 2 12, Patrick Turley 4 3, Benjamin Grenier-Boley 19 20 21, Vincent Chouraki 19 20 21 22, Yoichiro Kamatani 23 24, Claudine Berr 25 26 27, Luc Letenneur 28 29, Didier Hannequin 30 31, Philippe Amouyel 19 20 21 22, Anne Boland 32, Jean-François Deleuze 32, Emmanuelle Duron 33 34, Badri N Vardarajan 35, Christiane Reitz 36, Alison M Goate 37, Matthew J Huentelman 38, M Ilyas Kamboh 39, Eric B Larson 40 41, Ekaterina Rogaeva 42, Peter St George-Hyslop 42 43, Hakon Hakonarson 44 45 46, Walter A Kukull 47, Lindsay A Farrer 48, Lisa L Barnes 49 50 51, Thomas G Beach 52, F Yesim Demirci 39, Elizabeth Head 53, Christine M Hulette 54, Gregory A Jicha 55, John S K Kauwe 56, Jeffrey A Kaye 57, James B Leverenz 58, Allan I Levey 59, Andrew P Lieberman 60, Vernon S Pankratz 61, Wayne W Poon 62, Joseph F Quinn 63 64, Andrew J Saykin 65, Lon S Schneider 66, Amanda G Smith 67, Joshua A Sonnen 68 69, Robert A Stern 70, Vivianna M Van Deerlin 71, Linda J Van Eldik 53, Denise Harold 72, Giancarlo Russo 73, David C Rubinsztein 74 75, Anthony Bayer 76, Magda Tsolaki 77 78, Petra Proitsi 79, Nick C Fox 80 7, Harald Hampel 81 82 83 84, Michael J Owen 85 86, Simon Mead 87, Peter Passmore 88, Kevin Morgan 89, Markus M Nöthen 90 91, Martin Rossor 92, Michelle K Lupton 93 94, Per Hoffmann 90 91 95 96, Johannes Kornhuber 97, Brian Lawlor 98, Andrew McQuillin 99, Ammar Al-Chalabi 100 101, Joshua C Bis 102, Agustin Ruiz 103 104, Mercè Boada 103, Sudha Seshadri 105 106 107, Alexa Beiser 108 109 107, Kenneth Rice 110, Sven J van der Lee 111, Philip L De Jager 112, Daniel H Geschwind 113 114 115, Matthias Riemenschneider 116, Steffi Riedel-Heller 117, Jerome I Rotter 118, Gerhard Ransmayr 119, Bradley T Hyman 13 14, Carlos Cruchaga 120, Montserrat Alegret 103, Bendik Winsvold 121 122, Priit Palta 123 124, Kai-How Farh 125 3, Ester Cuenca-Leon 12 3 2, Nicholas Furlotte 126, Tobias Kurth 127, Lannie Ligthart 128, Gisela M Terwindt 129, Tobias Freilinger 130 131, Caroline Ran 132, Scott D Gordon 93, Guntram Borck 133, Hieab H H Adams 111 134, Terho Lehtimäki 135, Juho Wedenoja 136 137, Julie E Buring 138, Markus Schürks 139, Maria Hrafnsdottir 140, Jouke-Jan Hottenga 128 141, Brenda Penninx 142, Ville Artto 143, Mari Kaunisto 123, Salli Vepsäläinen 143, Nicholas G Martin 93, Grant W Montgomery 93 144, Mitja I Kurki 4 3 12 123, Eija Hämäläinen 123, Hailiang Huang 4 2 145, Jie Huang 146 147, Cynthia Sandor 148, Caleb Webber 148 11, Bertram Muller-Myhsok 149 150 151, Stefan Schreiber 152 153, Veikko Salomaa 154, Elizabeth Loehrer 155, Hartmut Göbel 156, Alfons Macaya 157, Patricia Pozo-Rosich 158 159, Thomas Hansen 160 161, Thomas Werge 161 162 163, Jaakko Kaprio 123 137, Andres Metspalu 124, Christian Kubisch 164, Michel D Ferrari 129, Andrea C Belin 132, Arn M J M van den Maagdenberg 165 129, John-Anker Zwart 166, Dorret Boomsma 167 128, Nicholas Eriksson 126, Jes Olesen 160, Daniel I Chasman 168 14, Dale R Nyholt 169, Andreja Avbersek 170, Larry Baum 171, Samuel Berkovic 172, Jonathan Bradfield 173, Russell J Buono 174 175 176, Claudia B Catarino 170 177, Patrick Cossette 178, Peter De Jonghe 179 180 181, Chantal Depondt 182, Dennis Dlugos 183 184, Thomas N Ferraro 185 186, Jacqueline French 187, Helle Hjalgrim 188, Jennifer Jamnadas-Khoda 170 189, Reetta Kälviäinen 190 191, Wolfram S Kunz 192 193, Holger Lerche 131, Costin Leu 194, Dick Lindhout 195 196, Warren Lo 197 198, Daniel Lowenstein 199, Mark McCormack 200 201, Rikke S Møller 202 203, Anne Molloy 204, Ping-Wing Ng 205 206, Karen Oliver 207, Michael Privitera 208 209, Rodney Radtke 210, Ann-Kathrin Ruppert 211, Thomas Sander 211, Steven Schachter 212 13 14, Christoph Schankin 213 214, Ingrid Scheffer 215 216 217, Susanne Schoch 218, Sanjay M Sisodiya 219 220, Philip Smith 221, Michael Sperling 222, Pasquale Striano 223, Rainer Surges 224 225, G Neil Thomas 226, Frank Visscher 227, Christopher D Whelan 200, Federico Zara 228, Erin L Heinzen 229, Anthony Marson 230 231, Felicitas Becker 232 233, Hans Stroink 234, Fritz Zimprich 235, Thomas Gasser 236 237, Raphael Gibbs 238, Peter Heutink 237 236, Maria Martinez 239 240, Huw R Morris 219, Manu Sharma 241, Mina Ryten 219, Kin Y Mok 8 242, Sara Pulit 243 244 3, Steve Bevan 245, Elizabeth Holliday 246, John Attia 247 248, Thomas Battey 12 249, Giorgio Boncoraglio 250 251, Vincent Thijs 217 252, Wei-Min Chen 253, Braxton Mitchell 254 255, Peter Rothwell 256, Pankaj Sharma 257 258, Cathie Sudlow 259, Astrid Vicente 260 261, Hugh Markus 262, Christina Kourkoulis 3 263 12, Joana Pera 264, Miriam Raffeld 3 12 263 265, Scott Silliman 266, Vesna Boraska Perica 267, Laura M Thornton 268, Laura M Huckins 269, N William Rayner 270 271 272, Cathryn M Lewis 273, Monica Gratacos 274, Filip Rybakowski 275, Anna Keski-Rahkonen 276, Anu Raevuori 277 276, James I Hudson 278, Ted Reichborn-Kjennerud 279 280, Palmiero Monteleone 281, Andreas Karwautz 282, Katrin Mannik 124 283, Jessica H Baker 268, Julie K O’Toole 284, Sara E Trace 285, Oliver S P Davis 286, Sietske G Helder 287 273, Stefan Ehrlich 288, Beate Herpertz-Dahlmann 289, Unna N Danner 290 291, Annemarie A van Elburg 290 291, Maurizio Clementi 292, Monica Forzan 293, Elisa Docampo 294 295, Jolanta Lissowska 296, Joanna Hauser 297, Alfonso Tortorella 298, Mario Maj 299, Fragiskos Gonidakis 300, Konstantinos Tziouvas 301, Hana Papezova 302 303, Zeynep Yilmaz 268, Gudrun Wagner 304, Sarah Cohen-Woods 305, Stefan Herms 90 91 95 96, Antonio Julià 306, Raquel Rabionet 307 308 309 310, Danielle M Dick 311, Samuli Ripatti 123 137 312, Ole A Andreassen 313 314, Thomas Espeseth 313 315 316, Astri J Lundervold 317 316, Vidar M Steen 318 319, Dalila Pinto 320 321 322 323, Stephen W Scherer 324 325, Harald Aschauer 326, Alexandra Schosser 327 328, Lars Alfredsson 329, Leonid Padyukov 330, Katherine A Halmi 331, James Mitchell 332 333, Michael Strober 334, Andrew W Bergen 335 336, Walter Kaye 337, Jin Peng Szatkiewicz 268, Bru Cormand 307 308 309 338, Josep Antoni Ramos-Quiroga 339 340 341 342, Cristina Sánchez-Mora 340 339 341, Marta Ribasés 340 339 341, Miguel Casas 343 344 339 345, Amaia Hervas 346, Maria Jesús Arranz 347, Jan Haavik 348 349, Tetyana Zayats 348 4, Stefan Johansson 350 319, Nigel Williams 10, Astrid Dempfle 351, Aribert Rothenberger 352, Jonna Kuntsi 353, Robert D Oades 354, Tobias Banaschewski 355, Barbara Franke 356 357 358, Jan K Buitelaar 359 360, Alejandro Arias Vasquez 361, Alysa E Doyle 263 14, Andreas Reif 362, Klaus-Peter Lesch 363 364 365, Christine Freitag 366, Olga Rivero 365, Haukur Palmason 140, Marcel Romanos 367, Kate Langley 368 85, Marcella Rietschel 369, Stephanie H Witt 369, Soeren Dalsgaard 370 163 371, Anders D Børglum 372 163 373 374, Irwin Waldman 375, Beth Wilmot 376, Nikolas Molly 377, Claiton H D Bau 378 379, Jennifer Crosbie 380 381, Russell Schachar 382 381, Sandra K Loo 383, James J McGough 384, Eugenio H Grevet 379 385, Sarah E Medland 93, Elise Robinson 4 2 6, Lauren A Weiss 386 387 388, Elena Bacchelli 389, Anthony Bailey 390 391, Vanessa Bal 386 387 388, Agatino Battaglia 392, Catalina Betancur 393, Patrick Bolton 353 394, Rita Cantor 395, Patrícia Celestino-Soper 396, Geraldine Dawson 397, Silvia De Rubeis 320 321 398, Frederico Duque 399 400, Andrew Green 401 402, Sabine M Klauck 403, Marion Leboyer 404 405 406, Pat Levitt 407 66, Elena Maestrini 389, Shrikant Mane 408 409, Daniel Moreno- De-Luca 410, Jeremy Parr 411 412 413, Regina Regan 402 414, Abraham Reichenberg 269, Sven Sandin 320 321 415, Jacob Vorstman 416 417, Thomas Wassink 418, Ellen Wijsman 419 110, Edwin Cook 420, Susan Santangelo 421 422, Richard Delorme 423 424, Bernadette Rogé 425 426 427, Tiago Magalhaes 414 428, Dan Arking 429, Thomas G Schulze 430 431 369 432 433, Robert C Thompson 434 435, Jana Strohmaier 369 436, Keith Matthews 437 438, Ingrid Melle 439 440, Derek Morris 441, Douglas Blackwood 442, Andrew McIntosh 442, Sarah E Bergen 415, Martin Schalling 443 444, Stéphane Jamain 404 405 406, Anna Maaser 91 90, Sascha B Fischer 95 445, Céline S Reinbold 95 445, Janice M Fullerton 446 447, José Guzman-Parra 448 449, Fermin Mayoral 448 449, Peter R Schofield 446 447, Sven Cichon 95 445 450, Thomas W Mühleisen 450 445, Franziska Degenhardt 451, Johannes Schumacher 451, Michael Bauer 452, Philip B Mitchell 453 454, Elliot S Gershon 455, John Rice 456, James B Potash 432, Peter P Zandi 457, Nick Craddock 85, I Nicol Ferrier 411, Martin Alda 458 459, Guy A Rouleau 460 461, Gustavo Turecki 462, Roel Ophoff 463 464, Carlos Pato 465, Adebayo Anjorin 466, Eli Stahl 269 312, Markus Leber 467, Piotr M Czerski 468, Cristiana Cruceanu 469 470, Ian R Jones 471, Danielle Posthuma 472 473, Till F M Andlauer 149 474, Andreas J Forstner 91 90 96 95 475, Fabian Streit 369, Bernhard T Baune 476, Tracy Air 476, Grant Sinnamon 477 478, Naomi R Wray 144 479, Donald J MacIntyre 480, David Porteous 481, Georg Homuth 482, Margarita Rivera 483 273, Jakob Grove 163 373 372 484, Christel M Middeldorp 485 486 128, Ian Hickie 487, Michele Pergadia 120, Divya Mehta 488 489, Johannes H Smit 142 490 491, Rick Jansen 142, Eco de Geus 128 490, Erin Dunn 12 492, Qingqin S Li 493, Matthias Nauck 494 495, Robert A Schoevers 496, Aartjan Tf Beekman 142 497, James A Knowles 498, Alexander Viktorin 415, Paul Arnold 499 500 417, Cathy L Barr 501 382 381, Gabriel Bedoya-Berrio 502, O Joseph Bienvenu 503, Helena Brentani 504, Christie Burton 382, Beatriz Camarena 505, Carolina Cappi 504, Danielle Cath 506 507, Maria Cavallini 508, Daniele Cusi 509, Sabrina Darrow 510, Damiaan Denys 511 512, Eske M Derks 93, Andrea Dietrich 513 514, Thomas Fernandez 515, Martijn Figee 511 320, Nelson Freimer 463, Gloria Gerber 12, Marco Grados 432, Erica Greenberg 263, Gregory L Hanna 435, Andreas Hartmann 516 517 518, Matthew E Hirschtritt 386 388, Pieter J Hoekstra 514, Alden Huang 519 384, Chaim Huyser 520 521, Cornelia Illmann 263, Michael Jenike 14, Samuel Kuperman 522, Bennett Leventhal 510, Christine Lochner 523, Gholson J Lyon 524, Fabio Macciardi 525, Marcos Madruga-Garrido 526, Irene A Malaty 527, Athanasios Maras 528, Lauren McGrath 529, Eurípedes C Miguel 530, Pablo Mir 531 532, Gerald Nestadt 432, Humberto Nicolini 533 534, Michael S Okun 535 536 537, Andrew Pakstis 409, Peristera Paschou 538, John Piacentini 384, Christopher Pittenger 539, Kerstin Plessen 540 541, Vasily Ramensky 542, Eliana M Ramos 543, Victor Reus 386 388, Margaret A Richter 544 545, Mark A Riddle 503, Mary M Robertson 546, Veit Roessner 547, Maria Rosário 548 549, Jack F Samuels 432, Paul Sandor 545 550 551, Dan J Stein 552 523, Fotis Tsetsos 553, Filip Van Nieuwerburgh 554, Sarah Weatherall 12, Jens R Wendland 555, Tomasz Wolanczyk 556, Yulia Worbe 557 558 559, Gwyneth Zai 545, Fernando S Goes 432, Nicole McLaughlin 560 561, Paul S Nestadt 432, Hans-Jorgen Grabe 562, Christel Depienne 563 564 565, Anuar Konkashbaev 566, Nuria Lanzagorta 534, Ana Valencia-Duarte 567 568, Elvira Bramon 99, Nancy Buccola 569, Wiepke Cahn 570, Murray Cairns 571 572 573, Siow A Chong 574, David Cohen 575 576, Benedicto Crespo-Facorro 577 341, James Crowley 285, Michael Davidson 578 579, Lynn DeLisi 580 14, Timothy Dinan 581 582, Gary Donohoe 583, Elodie Drapeau 269 320 321, Jubao Duan 584 585, Lieuwe Haan 511 586, David Hougaard 587, Sena Karachanak-Yankova 588, Andrey Khrunin 589, Janis Klovins 590, Vaidutis Kučinskas 591, Jimmy Lee Chee Keong 592, Svetlana Limborska 593, Carmel Loughland 594 247, Jouko Lönnqvist 154 595, Brion Maher 457, Manuel Mattheisen 596 597 598, Colm McDonald 599 600, Kieran C Murphy 601, Igor Nenadic 602 603, Jim van Os 570 604 605, Christos Pantelis 606 607 217, Michele Pato 465, Tracey Petryshen 2 12, Digby Quested 608 609, Panos Roussos 269, Alan R Sanders 610 585, Ulrich Schall 247, Sibylle G Schwab 611, Kang Sim 612 613 574, Hon-Cheong So 614 615 616, Elisabeth Stögmann 235, Mythily Subramaniam 574 613, Draga Toncheva 588, John Waddington 200, James Walters 85 86, Mark Weiser 579 617, Wei Cheng 268, Robert Cloninger 618, David Curtis 619 620, Pablo V Gejman 585 610, Frans Henskens 621 622 248, Morten Mattingsdal 439 623, Sang-Yun Oh 624 625, Rodney Scott 247 248 626, Bradley Webb 627, Gerome Breen 628 629, Claire Churchhouse 4 2 3, Cynthia M Bulik 630 415, Mark Daly 4 2 3, Martin Dichgans 15 150, Stephen V Faraone 631, Rita Guerreiro 7 8, Peter Holmans 10, Kenneth S Kendler 632, Bobby Koeleman 633, Carol A Mathews 634 537, Alkes Price 3 6, Jeremiah Scharf 2 3 12 12 635 13 14, Pamela Sklar 269, Julie Williams 10 11, Nicholas W Wood 8 619, Chris Cotsapas 3 636, Aarno Palotie 4 2 3 12 13 14 123, Jordan W Smoller 2 12, Patrick Sullivan 630 637, Jonathan Rosand 3 12 13 14, Aiden Corvin 638 639, Benjamin M Neale 1 2 3, Jonathan M Schott 80, Richard Anney 85 86, Josephine Elia 640 641, Maria Grigoroiu-Serbanescu 642, Howard J Edenberg 643, Robin Murray 353Affiliations expand
- PMID: 29930110
- PMCID: PMC6097237
- DOI: 10.1126/science.aap8757
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.
