A genome-wide association study of outcome from traumatic brain injury.
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Authors
Kals, Mart
Kunzmann, Kevin
Parodi, Livia
Radmanesh, Farid
Wilson, Lindsay
Izzy, Saef
Anderson, Christopher D
Puccio, Ava M
Okonkwo, David O
Temkin, Nancy
Steyerberg, Ewout W
Stein, Murray B
Manley, Geoff T
Maas, Andrew IR
Richardson, Sylvia
Diaz-Arrastia, Ramon
Palotie, Aarno
Ripatti, Samuli
Rosand, Jonathan
Menon, David K
Genetic Associations In Neurotrauma (GAIN) Consortium (with contribution from the CENTER-TBI, TRACK-TBI, CABI, MGB, and TBIcare studies)
Publication Date
2022-03Journal Title
EBioMedicine
ISSN
2352-3964
Publisher
Elsevier BV
Volume
77
Number
103933
Pages
103933
Type
Article
This Version
VoR
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Kals, M., Kunzmann, K., Parodi, L., Radmanesh, F., Wilson, L., Izzy, S., Anderson, C. D., et al. (2022). A genome-wide association study of outcome from traumatic brain injury.. EBioMedicine, 77 (103933), 103933. https://doi.org/10.1016/j.ebiom.2022.103933
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, Brain Injuries, Traumatic, Genome-Wide Association Study, Humans, Mannose-Binding Lectin, Prospective Studies, Transcriptome
Sponsorship
European Commission (602150)
Identifiers
External DOI: https://doi.org/10.1016/j.ebiom.2022.103933
This record's URL: https://www.repository.cam.ac.uk/handle/1810/337108
Rights
Attribution-NonCommercial-NoDerivatives 4.0 International
Licence URL: https://creativecommons.org/licenses/by-nc-nd/4.0/
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