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.
| Original language | English |
|---|---|
| Article number | 103933 |
| Number of pages | 12 |
| Journal | EBioMedicine |
| Volume | 77 |
| DOIs | |
| Publication status | Published - Mar-2022 |
Keywords
- Consortia
- Genome-Wide association study
- Outcome
- Recovery
- Traumatic brain injury
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In: EBioMedicine, Vol. 77, 103933, 03.2022.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - A genome-wide association study of outcome from traumatic brain injury
AU - The Genetic Associations In Neurotrauma (GAIN) Consortium (with contribution from the CENTER-TBI, TRACK-TBI, CABI, MGB, and TBIcare studies)
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 - Jacobs, Bram
AU - van der Naalt, Joukje
N1 - Funding Information: The CENTER-TBI study was supported by an FP7 Grant from the European Union (Grant No. 602150); Hannelore Kohl Stiftung (Germany); Integra LifeSciences Corporation (USA); NeuroTrauma Sciences LLC (USA). Work for the analysis in this publication at the Broad Institute was supported by One Mind (USA). The TRACK-TBI consortium was supported by US Department of Defense (TBI Endpoints Development Initiative (Grant No. W81XWH-14-2-0176)); US Department of Defense (TRACK-TBI Precision Medicine (Grant No. W81XWH-18-2-0042)); US Department of Defense/MTEC (TRACK-TBI NETWORK (Grant No. W81XWH-15-9-0001)); NIH-NINDS (TRACK-TBI (Grant No. U01NS086090)); National Football League Scientific Advisory Board (TRACK-TBI LONGITUDINAL); United States Department of Energy (funding for a precision medicine collaboration); NeuroTrauma Sciences LLC (funding for TRACK-TBI data curation); One Mind (funding for TRACK-TBI patients stipends and support to clinical sites). The research was supported by institutional funding from the University of Turku (Finland), Turku University Hospital (Finland) and Mass General Brigham (USA). Funding Information: In addition, M.K. is supported by the Estonian Research Council (grant No. PUTJD817); S.I. is supported by a Neurocritical Care Society Research Fellowship; C.D.A. is supported by the American Heart Association (AHA 18SFRN34250007, AHA-Bugher 21SFRN812095) and the National Institutes of Health of the US (R01NS103924, U01NS069673); M.B.S. is supported by NINDS and the US Department of Defense; S. Richardson is supported by the MRC Biostatistics Unit; D.K.M. is supported by the Cambridge NIHR Biomedical Research Centre grant. Funding Information: 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. Funding Information: We thank the Cambridge University Hospitals Genomic Laboratory, Cambridge University Hospitals NHS Foundation Trust for undertaking DNA extraction for the CENTER-TBI and CABI cohorts. We thank Mass General Brigham Biobank for providing samples, genomic data, and health information data. The CENTER-TBI study was supported by an FP7 Grant from the European Union (Grant No. 602150); Hannelore Kohl Stiftung (Germany); Integra LifeSciences Corporation (USA); NeuroTrauma Sciences LLC (USA). Work for the analysis in this publication at the Broad Institute was supported by One Mind (USA). The TRACK-TBI consortium was supported by US Department of Defense (TBI Endpoints Development Initiative (Grant No. W81XWH-14-2-0176)); US Department of Defense (TRACK-TBI Precision Medicine (Grant No. W81XWH-18-2-0042)); US Department of Defense/MTEC (TRACK-TBI NETWORK (Grant No. W81XWH-15-9-0001)); NIH-NINDS (TRACK-TBI (Grant No. U01NS086090)); National Football League Scientific Advisory Board (TRACK-TBI LONGITUDINAL); United States Department of Energy (funding for a precision medicine collaboration); NeuroTrauma Sciences LLC (funding for TRACK-TBI data curation); One Mind (funding for TRACK-TBI patients stipends and support to clinical sites). The research was supported by institutional funding from the University of Turku (Finland), Turku University Hospital (Finland) and Mass General Brigham (USA). In addition, M.K. is supported by the Estonian Research Council (grant No. PUTJD817); S.I. is supported by a Neurocritical Care Society Research Fellowship; C.D.A. is supported by the American Heart Association (AHA 18SFRN34250007, AHA-Bugher 21SFRN812095) and the National Institutes of Health of the US (R01NS103924, U01NS069673); M.B.S. is supported by NINDS and the US Department of Defense; S. Richardson is supported by the MRC Biostatistics Unit; D.K.M. is supported by the Cambridge NIHR Biomedical Research Centre grant. GWAS summary statistics from the European ancestry and the trans-ancestry meta-analysis and TWAS summary statistics are made available through zenodo.org (DOI: 10.5281/zenodo.5826420). Publisher Copyright: © 2022
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 - Consortia
KW - Genome-Wide association study
KW - Outcome
KW - Recovery
KW - Traumatic brain injury
U2 - 10.1016/j.ebiom.2022.103933
DO - 10.1016/j.ebiom.2022.103933
M3 - Article
C2 - 35301180
AN - SCOPUS:85126327411
SN - 2352-3964
VL - 77
JO - EBioMedicine
JF - EBioMedicine
M1 - 103933
ER -