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, Geoffrey A. Manley, Andrew I.R. Maas, Sylvia Richardson, Ramon Diaz‐Arrastia, Aarno Palotie, Samuli Ripatti, Jonathan Rosand, David Menon, Cecilia Åkerlund, Krisztina Amrein, Nada Andelic, Lasse Andreassen, Audny Anke, Anna Degli 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 Bražinová, 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 Coles, Jamie D. Cooper, Marta Correia, Amra Čović, Nicola Curry, Endre Czeiter, Marek Czosnyka, Claire Dahyot‐Fizelier, Paul Dark, Helen Dawes, Véronique De Keyser, Vincent Degos, Françesco Della Corte, Hugo den Boogert, Bart Depreitere, Đula Đilvesi, Abhishek Dixit, Emma Donoghue, Jens P. Dreier, Guy‐Loup 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 Golubović, Pedro A. Gómez, Johannes Gratz, Benjamin Gravesteijn, Francesca Grossi
Abstract
BackgroundFactors 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.MethodsWe 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.FindingsThe 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).InterpretationWhile 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.FundingA full list of funding bodies that contributed to this study can be found in the Acknowledgements section.