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

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.
Competing Interests: Declaration of interests K.K. is now an employee of Boehringer Ingelheim. S.I. declares royalties or licenses with McGraw Hill education. L.W. reports receiving consultancy fees from Vasopharm and Novartis outside the submitted work. C.D.A. declares sponsored research support from Bayer AG and consulting fees from ApoPharma. R.DA. declares consultation for MesoScale Discoveries and Ischemix, Inc.; stocks/stock options in BrainBox Solutions, Inc. and NovaSignal, Inc.; and has received equipment, materials, drugs, medical writing, gifts or other services from MesoScale Discoveries. M.B.S. declares advisory work and stock options with Oxeia Biopharmaceuticals. A.I.R.M. serves as an advisory board member for PressuraNeuro. D.K.M. declares the following conflicts of interest outside the scope of the submitted work: collaborative grant funding, consultancy fees, or educational grants from Lantmannen AB, GlaxoSmithKline Ltd., PressuraNeuro Ltd., Calico LLC, NeuroTrauma Sciences LLC, and Integra Neurosciences. He acts as a Trustee for Queens’ College (Cambridge, UK), the Intensive Care National Audit and Research Centre (London, UK), and is Chair and Trustee of the European Brain Injury Consortium. J.R. declares participation on advisory boards for Takeda Pharmaceuticals, Pfizer and Boehringer Ingelheim, outside the scope of the submitted work. The remaining authors declare no competing interests.
(Copyright © 2022. Published by Elsevier B.V.)