Journal
EBIOMEDICINE
Volume 77, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.ebiom.2022.103933
Keywords
Traumatic brain injury; Genome-Wide association study; Outcome; Recovery; Consortia
Funding
- European Union
- Hannelore Kohl Stiftung (Germany)
- Integra LifeSciences Corporation (USA)
- NeuroTrauma Sciences LLC (USA)
- One Mind (USA)
- US Department of Defense (TBI Endpoints Development Initiative)
- US Department of Defense
- US Department of Defense/MTEC (TRACK-TBI NETWORK)
- NIH-NINDS
- National Football League Scientific Advisory Board
- United States Department of Energy
- NeuroTrauma Sciences LLC
- One Mind
- University of Turku (Finland) [602150]
- Turku University Hospital (Finland)
- Mass General Brigham (USA)
- Estonian Research Council
- Neurocritical Care Society
- American Heart Association [W81XWH-14-2-0176]
- National Institutes of Health of the US [W81XWH-18-2-0042]
- NINDS [W81XWH-15-9-0001]
- MRC Biostatistics Unit [U01NS086090]
- Cambridge NIHR Biomedical Research Centre
- [PUTJD817]
- [AHA 18SFRN34250007]
- [AHA-Bugher 21SFRN812095]
- [R01NS103924]
- [U01NS069673]
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This study is the first genome-and transcriptome-wide association studies of genetic effects on outcome in traumatic brain injury (TBI). While no genetic variants with genome-wide significance were found, the overall heritability estimate is consistent with the hypothesis that common genetic variation substantially contributes to inter-individual variability in TBI outcome.
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.& nbsp;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.& nbsp;Findings The estimated heritability of TBI outcome was 0.26. GWAS revealed no genetic variants with genome-wide significance (p < 5 x 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 x 10(-4)).& nbsp;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.& nbsp;Copyright (C)& nbsp;2022 Published by Elsevier B.V.
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