TY - JOUR
T1 - A genome-wide association study of outcome from traumatic brain injury
AU - Kals, Mart
AU - Kunzmann, Kevin
AU - Parodi, Livia
AU - Radmanesh, Farid
AU - Wilson, Lindsay
AU - Izzy, Saef
AU - Anderson, Christopher D
AU - Puccio, Ava M
AU - Okonkwo, David O
AU - Temkin, Nancy
AU - Steyerberg, Ewout W
AU - Stein, Murray B
AU - Manley, Geoff T
AU - Maas, Andrew I R
AU - Richardson, Sylvia
AU - Diaz-Arrastia, Ramon
AU - Palotie, Aarno
AU - Ripatti, Samuli
AU - Rosand, Jonathan
AU - Menon, David K
AU - Genetic Associations In Neurotrauma (GAIN) Consortium (with contribution from the CENTER-TBI, TRACK-TBI, CABI, MGB, and TBIcare studies)
A2 - Kondziella, Daniel
A2 - Fabricius, Martin Ejler
N1 - Copyright © 2022. Published by Elsevier B.V.
PY - 2022/3
Y1 - 2022/3
N2 - 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.
AB - 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.
KW - Brain Injuries, Traumatic/genetics
KW - Genome-Wide Association Study/methods
KW - Humans
KW - Mannose-Binding Lectin/genetics
KW - Prospective Studies
KW - Transcriptome
KW - Consortia
KW - Genome-Wide association study
KW - Traumatic brain injury
KW - Outcome
KW - Recovery
UR - http://www.scopus.com/inward/record.url?scp=85126327411&partnerID=8YFLogxK
U2 - 10.1016/j.ebiom.2022.103933
DO - 10.1016/j.ebiom.2022.103933
M3 - Journal article
C2 - 35301180
SN - 2352-3964
VL - 77
SP - 1
EP - 12
JO - EBioMedicine
JF - EBioMedicine
M1 - 103933
ER -