A - 7 Genome-Wide Association Study of Traumatic Brain Injury in U.S. Military Veterans

Large-scale genetic studies of traumatic brain injury (TBI) are lacking; thus, our understanding of the influence of genetic factors on TBI risk and recovery is incomplete. This study aimed to conduct a genome-wide association study (GWAS) of TBI in VA Million Veteran Program (MVP) enrollees.Participants included a multi-ancestry cohort (European, African, and Hispanic ancestries; N = 304,485; 111,494 TBI cases, 192,991 controls). TBI was assessed using MVP survey data and ICD codes from electronic health records. GWAS was performed using logistic regression in PLINK, and FUMA was used for post-GWAS analysis. Genetic correlations between TBI and several health domains (risk-taking behaviors, psychiatric disorders, neurocognitive variables, and brain morphometrics) were also evaluated.SNP-based heritability was 0.060 (SE = 0.004, p = 7.83x10-66). GWAS analysis identified 15 genome-wide significant loci at p < 5x10-8. Gene-based analyses revealed 14 gene-wide significant genes, including NCAM1, APOE, FTO, and FOXP2. Gene tissue expression analysis identified the brain as significantly enriched, particularly in the frontal cortex, anterior cingulate cortex, and nucleus accumbens. Genetic correlations with TBI were significant for risk-taking behaviors and psychiatric disorders, but generally non-significant for neurocognitive and brain morphometric variables. The strongest genetic correlation was with PTSD (rg = 0.69, SE = 0.04, p = 2.5x10-75).This first well-powered GWAS of TBI showed that TBI is a heritable trait and identified 15 loci including genes relevant to TBI biology. Findings also revealed high genetic correlations with psychiatric and risk-taking traits, significantly advancing understanding of the genetic basis of TBI. Results set the stage for future TBI GWASs that focus on diversity and chronicity of symptom sequelae.