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

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 Rosand, David K MenonGenetic Associations In Neurotrauma (GAIN) Consortium (with contribution from the CENTER-TBI, TRACK-TBI, CABI, MGB, and TBIcare studies), Daniel Kondziella (Medlem af forfattergruppering), Martin Ejler Fabricius (Medlem af forfattergruppering)

27 Citationer (Scopus)

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.

OriginalsprogEngelsk
Artikelnummer103933
TidsskriftEBioMedicine
Vol/bind77
Sider (fra-til)1-12
Antal sider12
DOI
StatusUdgivet - mar. 2022

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