Suchergebnisse

Traumatic brain injury (TBI) contributes to the increased rates of suicide and post-traumatic stress disorder in military personnel and veterans, and it is also associated with the risk for neurodegenerative and psychiatric disorders. A cross-phenotype high-resolution polygenic risk score (PRS) analysis of persistent post-concussive symptoms (PCS) was conducted in 845 U.S. Army soldiers who sustained TBI during their deployment. We used a prospective longitudinal survey of three brigade combat teams to assess deployment-acquired TBI and persistent physical, cognitive, and emotional PCS. PRS was derived from summary statistics of large genome-wide association studies of Alzheimer's disease, Parkinson's disease, schizophrenia, bipolar disorder, and major depressive disorder (MDD); and for years of schooling, college completion, childhood intelligence, infant head circumference (IHC), and adult intracranial volume. Although our study had more than 95% of statistical power to detect moderate-to-large effect sizes, no association was observed with neurodegenerative and psychiatric disorders, suggesting that persistent PCS does not share genetic components with these traits to a moderate-to-large degree. We observed a significant finding: subjects with high IHC PRS recovered better from cognitive/emotional persistent PCS than the other individuals (R2 = 1.11%; p = 3.37 × 10−3). Enrichment analysis identified two significant Gene Ontology (GO) terms related to this result: GO:0050839∼Cell adhesion molecule binding (p = 8.9 × 10−6) and GO:0050905∼Neuromuscular process (p = 9.8 × 10−5). In summary, our study indicated that the genetic predisposition to persistent PCS after TBI does not have substantial overlap with neurodegenerative and psychiatric diseases, but mechanisms related to early brain growth may be involved.

Posttraumatic stress disorder (PTSD) is a chronic and disabling psychiatric disorder prevalent in military veterans. Epigenetic mechanisms have been implicated in the etiology of PTSD, with DNA methylation being the most studied to identify novel molecular biomarkers associated with this disorder. We performed one of the largest single-sample epigenome-wide association studies (EWAS) of PTSD to date. Our sample included 1135 male European–American U.S. veterans who participated in the National Health and Resilience in Veterans Study (NHRVS). DNA was collected from saliva samples and the Illumina HumanMethylation EPIC BeadChip was used for the methylation analysis. PTSD was assessed using the PTSD Checklist. An EWAS was conducted using linear regression adjusted for age, cell-type proportions, first 10 principal components, and smoking status. After Bonferroni correction, we identified six genome-wide significant (GWS) CpG sites associated with past-month PTSD and three CpGs with lifetime PTSD (p(range) = 10(−10)–10(−8)). These CpG sites map to genes involved in immune function, transcription regulation, axonal guidance, cell signaling, and protein binding. Among these, SENP7, which is involved in transcription regulation and has been linked to risk-taking behavior and alcohol consumption in genome-wide association studies, replicated in an independent veteran cohort and was downregulated in medial orbitofrontal cortex of PTSD postmortem brain tissue. These findings suggest potential epigenetic biomarkers of PTSD that may help inform the pathophysiology of this disorder in veterans and other trauma-affected populations.

The human oxytocin system is implicated in social behavior and stress recovery. Polymorphisms in the oxytocin receptor gene (OXTR) may interact with attachment style to predict stress-related psychopathology like posttraumatic stress disorder (PTSD). The objective of this study was to examine independent and interactive effects of the OXTR single nucleotide polymorphism (SNP) rs53576, which has been associated with stress reactivity, support-seeking, and PTSD in prior studies, and attachment style on risk for PTSD in a nationally representative sample of 2163 European-American (EA) U.S. military veterans who participated in two independent waves of the National Health and Resilience in Veterans Study (NHRVS). Results revealed that insecure attachment style [adjusted odds ratio (OR)=4.29; p<0.001] and the interaction of rs53576 and attachment style (OR=2.58, p=0.02) were associated with probable lifetime PTSD. Among individuals with the minor A allele, the prevalence of probable PTSD was significantly higher among those with an insecure attachment style (23.9%) than those with a secure attachment style (2.0%), equivalent to an adjusted OR of 10.7. We attempted to replicate these findings by utilizing dense marker data from a genome-wide association study of 2,215 high-risk civilians; one OXTR variant, though not rs53576, was associated with PTSD. Exploratory analyses in the veteran sample revealed that the interaction between this variant and attachment style predicting probable PTSD approached statistical significance. Results indicate that polymorphisms in the OXTR gene and attachment style may contribute to vulnerability to PTSD in U.S. military veterans.

Insomnia is a worldwide problem with substantial deleterious health effects. Twin studies have shown a heritable basis for various sleep-related traits, including insomnia, but robust genetic risk variants have just recently begun to be identified. We conducted genome-wide association studies (GWAS) of soldiers in the Army Study To Assess Risk and Resilience in Servicemembers (STARRS). GWAS were carried out separately for each ancestral group (EUR, AFR, LAT) using logistic regression for each of the STARRS component studies (including 3,237 cases and 14,414 controls), and then meta-analysis was conducted across studies and ancestral groups. Heritability (SNP-based) for lifetime insomnia disorder was significant (h2g = 0.115, p = 1.78 × 10-4 in EUR). A meta-analysis including three ancestral groups and three study cohorts revealed a genome-wide significant locus on Chr 7 (q11.22) (top SNP rs186736700, OR = 0.607, p = 4.88 × 10-9) and a genome-wide significant gene-based association (p = 7.61 × 10-7) in EUR for RFX3 on Chr 9. Polygenic risk for sleeplessness/insomnia severity in UK Biobank was significantly positively associated with likelihood of insomnia disorder in STARRS. Genetic contributions to insomnia disorder in STARRS were significantly positively correlated with major depressive disorder (rg = 0.44, se = 0.22, p = 0.047) and type 2 diabetes (rg = 0.43, se = 0.20, p = 0.037), and negatively with morningness chronotype (rg = -0.34, se = 0.17, p = 0.039) and subjective well being (rg = -0.59, se = 0.23, p = 0.009) in external datasets. Insomnia associated loci may contribute to the genetic risk underlying a range of health conditions including psychiatric disorders and metabolic disease.

Acknowledgements We are grateful to the families who took part in GS:SFHS, the GPs and Scottish School of Primary Care for their help in recruiting them, and the whole GS team, which includes academic researchers, clinic staff, laboratory technicians, clerical workers, IT staff, statisticians and research managers. Funded by Scottish Government Health Department, Chief Scientist Office. Grant Number: CZD/16/6 National Institutes of Health. Grant Numbers: N01-HG-65403, HHSN268200782096C, RC2 DA028909, R01 DA12690, R01 DA12849, R01 DA18432, R01 AA11330, R01 AA017535, P50 AA12870, MSTP T32GM07205, CTSA 8UL1TR000142 NIH Genes, Environment and Health Initiative [GEI]. Grant Numbers: U01 HG004422, U01HG004438 Gene Environment Association Studies (GENEVA). Grant Number: U01 HG004446 Collaborative Study on the Genetics of Alcoholism. Grant Number: U10 AA008401 Collaborative Genetic Study of Nicotine Dependence. Grant Number: P01 CA089392 Family Study of Cocaine Dependence. Grant Number: R01 DA013423 National Institute on Alcohol Abuse and Alcoholism National Institute on Drug Abuse Dr Mortimer and Theresa Sackler Foundation Biotechnology and Biological Sciences Research Council (BBSRC) Medical Research Council (MRC) ; Peer reviewed ; Publisher PDF