A genome-wide association study of outcome from traumatic brain injury

Mart Kals; Kevin Kunzmann; Livia Parodi; Farid Radmanesh; Lindsay Wilson; Saef Izzy; Christopher D Anderson; Ava M Puccio; David O Okonkwo; Nancy Temkin; Ewout W Steyerberg; Murray B Stein; Geoff T Manley; Andrew I R Maas; Sylvia Richardson; Ramon Diaz-Arrastia; Aarno Palotie; Samuli Ripatti; Jonathan Rosand; David K Menon; Genetic Associations In Neurotrauma (GAIN) Consortium (with contribution from the CENTER-TBI, TRACK-TBI, CABI, MGB, and TBIcare studies)

doi:10.1016/j.ebiom.2022.103933

A genome-wide association study of outcome from traumatic brain injury

EBioMedicine. 2022 Mar:77:103933. doi: 10.1016/j.ebiom.2022.103933. Epub 2022 Mar 14.

Authors

Mart Kals¹, Kevin Kunzmann², Livia Parodi³, Farid Radmanesh⁴, Lindsay Wilson⁵, Saef Izzy⁴, Christopher D Anderson⁶, Ava M Puccio⁷, David O Okonkwo⁷, Nancy Temkin⁸, Ewout W Steyerberg⁹, Murray B Stein¹⁰, Geoff T Manley¹¹, Andrew I R Maas¹², Sylvia Richardson², Ramon Diaz-Arrastia¹³, Aarno Palotie¹⁴, Samuli Ripatti¹⁵, Jonathan Rosand¹⁶, David K Menon¹⁷; Genetic Associations In Neurotrauma (GAIN) Consortium (with contribution from the CENTER-TBI, TRACK-TBI, CABI, MGB, and TBIcare studies)

Collaborators

Genetic Associations In Neurotrauma (GAIN) Consortium (with contribution from the CENTER-TBI, TRACK-TBI, CABI, MGB, and TBIcare studies):
Cecilia Åkerlund, Krisztina Amrein, Nada Andelic, Lasse Andreassen, Audny Anke, Anna Antoni, Gérard Audibert, Philippe Azouvi, Maria Luisa Azzolini, Ronald Bartels, Pál Barzó, Romuald Beauvais, Ronny Beer, Bo-Michael Bellander, Antonio Belli, Habib Benali, Maurizio Berardino, Luigi Beretta, Morten Blaabjerg, Peter Bragge, Alexandra Brazinova, Vibeke Brinck, Joanne Brooker, Camilla Brorsson, Andras Buki, Monika Bullinger, Manuel Cabeleira, Alessio Caccioppola, Emiliana Calappi, Maria Rosa Calvi, Peter Cameron, Guillermo Carbayo Lozano, Marco Carbonara, Simona Cavallo, Giorgio Chevallard, Arturo Chieregato, Giuseppe Citerio, Hans Clusmann, Mark Coburn, Jonathan P Coles, Jamie D Cooper, Marta Correia, Amra Čović, Nicola Curry, Endre Czeiter, Marek Czosnyka, Claire DahyotFizelier, Paul Dark, Helen Dawes, Véronique De Keyser, Vincent Degos, Francesco Della Corte, Hugo den Boogert, Bart Depreitere, Đula Đilvesi, Abhishek Dixit, Emma Donoghue, Jens Dreier, GuyLoup Dulière, Ari Ercole, Patrick Esser, Erzsébet Ezer, Martin Fabricius, Valery L Feigin, Kelly Foks, Shirin Frisvold, Alex Furmanov, Pablo Gagliardo, Damien Galanaud, Dashiell Gantner, Guoyi Gao, Pradeep George, Alexandre Ghuysen, Lelde Giga, Ben Glocker, Jagoš Golubovic, Pedro A Gomez, Johannes Gratz, Benjamin Gravesteijn, Francesca Grossi, Russell L Gruen, Deepak Gupta, Juanita A Haagsma, Iain Haitsma, Raimund Helbok, Eirik Helseth, Lindsay Horton, Jilske Huijben, Peter J A Hutchinson, Bram Jacobs, Stefan Jankowski, Mike Jarrett, Jiyao Jiang, Faye Johnson, Kelly Jones, Mladen Karan, Angelos G Kolias, Erwin Kompanje, Daniel Kondziella, Evgenios Kornaropoulos, LarsOwe Koskinen, Noémi Kovács, Ana Kowark, Alfonso Lagares, Linda Lanyon, Steven Laureys, Fiona Lecky, Didier Ledoux, Rolf Lefering, Valerie Legrand, Aurelie Lejeune, Leon Levi, Roger Lightfoot, Hester Lingsma, Andrew I R Maas, Ana M CastañoLeón, Marc Maegele, Marek Majdan, Alex Manara, Costanza Martino, Hugues Maréchal, Julia Mattern, Catherine McMahon, Béla Melegh, David K Menon, Tomas Menovsky, Ana Mikolic, Benoit Misset, Visakh Muraleedharan, Lynnette Murray, Ancuta Negru, David Nelson, Virginia F J Newcombe, Daan Nieboer, József Nyirádi, Otesile Olubukola, Matej Oresic, Fabrizio Ortolano, Aarno Palotie, Paul M Parizel, JeanFrançois Payen, Natascha Perera, Vincent Perlbarg, Paolo Persona, Wilco Peul, Anna Piippo-Karjalainen, Matti Pirinen, Dana Pisica, Horia Ples, Suzanne Polinder, Inigo Pomposo, Jussi P Posti, Louis Puybasset, Andreea Radoi, Arminas Ragauskas, Rahul Raj, Malinka Rambadagalla, Isabel Retel Helmrich, Jonathan Rhodes, Sylvia Richardson, Sophie Richter, Samuli Ripatti, Saulius Rocka, Cecilie Roe, Olav Roise, Jeffrey V Rosenfeld, Christina Rosenlund, Guy Rosenthal, Rolf Rossaint, Sandra Rossi, Daniel Rueckert, Martin Rusnák, Juan Sahuquillo, Oliver Sakowitz, Renan SanchezPorras, Janos Sandor, Nadine Schäfer, Silke Schmidt, Herbert Schoechl, Guus Schoonman, Rico Frederik Schou, Elisabeth Schwendenwein, Charlie Sewalt, Toril Skandsen, Peter Smielewski, Abayomi Sorinola, Emmanuel Stamatakis, Simon Stanworth, Robert Stevens, William Stewart, Ewout W Steyerberg, Nino Stocchetti, Nina Sundström, Riikka Takala, Viktória Tamás, Tomas Tamosuitis, Mark Steven Taylor, Braden Te Ao, Olli Tenovuo, Alice Theadom, Matt Thomas, Dick Tibboel, Marjolein Timmers, Christos Tolias, Tony Trapani, Cristina Maria Tudora, Andreas Unterberg, Peter Vajkoczy, Shirley Vallance, Egils Valeinis, Zoltán Vámos, Mathieu van der Jagt, Gregory van der Steen, Joukje van der Naalt, Jeroen T J M van Dijck, Thomas A van Essen, Wim Van Hecke, Caroline van Heugten, Dominique Van Praag, Ernest van Veen, Thijs Vande Vyvere, Roel P J van Wijk, Alessia Vargiolu, Emmanuel Vega, Kimberley Velt, Jan Verheyden, Paul M Vespa, Anne Vik, Rimantas Vilcinis, Victor Volovici, Nicole von Steinbüchel, Daphne Voormolen, Petar Vulekovic, Kevin K W Wang, Eveline Wiegers, Guy Williams, Lindsay Wilson, Stefan Winzeck, Stefan Wolf, Zhihui Yang, Peter Ylén, Alexander Younsi, Frederick A Zeiler, Veronika Zelinkova, Agate Ziverte, Tommaso Zoerle, Saef Izzy, Farid Radmanesh, Janek Frantzén, Ari Katila, Henna-Rikka Maanpää, Jussi Tallus, Opeolu Adeoye, Neeraj Badjatia, Kim Boase, Jason Barber, Yelena Bodien, Randall Chesnut, John D Corrigan, Karen Crawford, Ramon Diaz-Arrastia, Sureyya Dikmen, Ann-Christine Duhaime, Richard Ellenbogen, Ramana Feeser, Adam R Ferguson, Brandon Foreman, Raquel Gardner, Etienne Gaudette, Joseph Giacino, Dana Goldman, Luis Gonzalez, Shankar Gopinath, Rao Gullapalli, Claude Hemphill, Gillian Hotz, Sonia Jain, Dirk Keene, Frederick K Korley, Joel Kramer, Natalie Kreitzer, Harvey Levin, Chris Lindsell, Joan Machamer, Christopher Madden, Geoffrey T Manley, Alastair Martin, Thomas McAllister, Michael McCrea, Randall Merchant, Pratik Mukherjee, Lindsay Nelson, Laura B Ngwenya, Florence Noel, Amber Nolan, David Okonkwo, Eva Palacios, Daniel Perl, Ava Puccio, Miri Rabinowitz, Claudia Robertson, Jonathan Rosand, Angelle Sander, Gabriella Satris, David Schnyer, Seth Seabury, Mark Sherer, Murray Stein, Sabrina Taylor, Nancy Temkin, Arthur Toga, Alex Valadka, Mary Vassar, John K Yue, Esther Yuh, Ross Zafonte

Affiliations

¹ Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland; Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.
² MRC Biostatistics Unit, Cambridge Institute of Public Health, University of Cambridge, Cambridge, United Kingdom.
³ Center for Genomic Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA CPZN-6810, USA; McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
⁵ Division of Psychology, University of Stirling, Stirling, United Kingdom.
⁶ McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
⁷ Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
⁸ Departments of Neurological Surgery and Biostatistics, University of Washington, Seattle, WA, USA.
⁹ Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, the Netherlands; Department of Public Health, Erasmus MC, Rotterdam, the Netherlands.
¹⁰ Department of Psychiatry, School of Medicine, and School of Public Health, University of California, San Diego, La Jolla, CA, USA.
¹¹ Department of Neurosurgery, University of California, San Francisco, CA, USA.
¹² Department of Neurosurgery, Antwerp University Hospital and University of Antwerp, Edegem, Belgium.
¹³ Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
¹⁴ Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland; Center for Genomic Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA CPZN-6810, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁵ Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Public Health, University of Helsinki, Helsinki, Finland.
¹⁶ Center for Genomic Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA CPZN-6810, USA; McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: [email protected].
¹⁷ Division of Anaesthesia, University of Cambridge, Addenbrooke's Hospital, Box 93, Addenbrooke's Hospital, Cambridge CB2 2QQ, United Kingdom. Electronic address: [email protected].

Abstract

Background: Factors such as age, pre-injury health, and injury severity, account for less than 35% of outcome variability in traumatic brain injury (TBI). While some residual outcome variability may be attributable to genetic factors, published candidate gene association studies have often been underpowered and subject to publication bias.

Methods: We performed the first genome- and transcriptome-wide association studies (GWAS, TWAS) of genetic effects on outcome in TBI. The study population consisted of 5268 patients from prospective European and US studies, who attended hospital within 24 h of TBI, and satisfied local protocols for computed tomography.

Findings: The estimated heritability of TBI outcome was 0·26. GWAS revealed no genetic variants with genome-wide significance (p < 5 × 10^-8), but identified 83 variants in 13 independent loci which met a lower pre-specified sub-genomic statistical threshold (p < 10^-5). Similarly, none of the genes tested in TWAS met tissue-wide significance. An exploratory analysis of 75 published candidate variants associated with 28 genes revealed one replicable variant (rs1800450 in the MBL2 gene) which retained significance after correction for multiple comparison (p = 5·24 × 10^-4).

Interpretation: While multiple novel loci reached less stringent thresholds, none achieved genome-wide significance. The overall heritability estimate, however, is consistent with the hypothesis that common genetic variation substantially contributes to inter-individual variability in TBI outcome. The meta-analytic approach to the GWAS and the availability of summary data allows for a continuous extension with additional cohorts as data becomes available.

Funding: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

Keywords: Consortia; Genome-Wide association study; Outcome; Recovery; Traumatic brain injury.

Publication types

Meta-Analysis

MeSH terms

Brain Injuries, Traumatic* / genetics
Genome-Wide Association Study / methods
Humans
Mannose-Binding Lectin* / genetics
Prospective Studies
Transcriptome

Substances

MBL2 protein, human
Mannose-Binding Lectin

Abstract

Publication types

MeSH terms

Substances

Grants and funding