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

The Genetic Associations In Neurotrauma (GAIN) Consortium (with contribution from the CENTER-TBI, TRACK-TBI, CABI, MGB, and TBIcare studies), Mart Kals, Kevin Kunzmann*, Livia Parodi, Farid Radmanesh, Lindsay Wilson, Saef Izzy, Christopher D. Anderson, Ava M. Puccio, David O. Okonkwo, Nancy Temkin, Ewout W. Steyerberg, Murray B. Stein, Geoff T. Manley, Andrew I.R. Maas, Sylvia Richardson, Ramon Diaz-Arrastia, Aarno Palotie, Samuli Ripatti, Jonathan RosandDavid K. Menon*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

20 Citations (Scopus)
44 Downloads (Pure)

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 languageEnglish
Article number103933
Number of pages12
JournalEBioMedicine
Volume77
DOIs
Publication statusPublished - Mar-2022

Keywords

  • Consortia
  • Genome-Wide association study
  • Outcome
  • Recovery
  • Traumatic brain injury

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