The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5–20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson’s disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations.

BACKGROUND Many studies report smaller hippocampal and amygdala volumes in posttraumatic stress disorder (PTSD), but findings have not always been consistent. Here, we present the results of a large-scale neuroimaging consortium study on PTSD conducted by the Psychiatric Genomics Consortium (PGC)–Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) PTSD Working Group. METHODS We analyzed neuroimaging and clinical data from 1868 subjects (794 PTSD patients) contributed by 16 cohorts, representing the largest neuroimaging study of PTSD to date. We assessed the volumes of eight subcortical structures (nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen, thalamus, and lateral ventricle). We used a standardized image-analysis and quality-control pipeline established by the ENIGMA consortium. RESULTS In a meta-analysis of all samples, we found significantly smaller hippocampi in subjects with current PTSD compared with trauma-exposed control subjects (Cohen’s d = −0.17, p = .00054), and smaller amygdalae (d = −0.11, p = .025), although the amygdala finding did not survive a significance level that was Bonferroni corrected for multiple subcortical region comparisons (p < .0063). CONCLUSIONS Our study is not subject to the biases of meta-analyses of published data, and it represents an important milestone in an ongoing collaborative effort to examine the neurobiological underpinnings of PTSD and the brain’s response to trauma.

OBJECTIVE -To evaluate the association between cognitive dysfunction and other barriers and glycemic control in older adults with diabetes.RESEARCH DESIGN AND METHODS -Patients over the age of 70 years presenting to a geriatric diabetes clinic were evaluated for barriers to successful diabetes management. Patients were screened for cognitive dysfunction with the Mini Mental State Examination (MMSE) and a clock-drawing test (CDT) scored by 1) a method validated by Mendez et al. and 2) a modified CDT (clock in a box [CIB]). Depression was evaluated with the Geriatric Depression Scale. Interview questionnaires surveyed activities of daily living (ADLs) and instrumental ADLs (IADLs), as well as other functional disabilities.RESULTS -Sixty patients (age 79 Ϯ 5 years, diabetes duration 14 Ϯ 13 years) were evaluated. Thirty-four percent of patients had low CIB (Յ5), and 38% of patients had low CDT (Յ13). Both CIB as well as CDT were inversely correlated with HbA 1c , suggesting that cognitive dysfunction is associated with poor glycemic control (r ϭ Ϫ0.37, P Ͻ 0.004 and r ϭ Ϫ0.38, P Ͻ 0.004, respectively). Thirty-three percent of patients had depressive symptoms with greater difficulty completing the tasks of the IADL survey (5.7 Ϯ 1.7 vs. 4.6 Ϯ 2.0; P Ͻ 0.03). These older adults with diabetes had a high incidence of functional disabilities, including hearing impairment (48%), vision impairment (53%), history of recent falls (33%), fear of falls (44%), and difficulty performing IADLs (39%).CONCLUSIONS -Older adults with diabetes have a high risk of undiagnosed cognitive dysfunction, depression, and functional disabilities. Cognitive dysfunction in this population is associated with poor diabetes control.

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Background Accumulating evidence suggests that post traumatic stress disorder (PTSD) may accelerate cellular aging and lead to premature morbidity and neurocognitive decline. Methods This study evaluated associations between PTSD and DNA methylation (DNAm) age using recently developed algorithms of cellular age by Horvath (2013) and Hannum et al. (2013). These estimates reflect accelerated aging when they exceed chronological age. We also examined if accelerated cellular age manifested in degraded neural integrity, indexed via diffusion tensor imaging. Results Among 281 male and female veterans of the conflicts in Iraq and Afghanistan, DNAm age was strongly related to chronological age (rs ~.88). Lifetime PTSD severity was associated with Hannum DNAm age estimates residualized for chronological age (β = .13, p= .032). Advanced DNAm age was associated with reduced integrity in the genu of the corpus callosum (β = −.17, p= .009) and indirectly linked to poorer working memory performance via this region (indirect β = − .05, p= .029). Horvath DNAm age estimates were not associated with PTSD or neural integrity. Conclusions Results provide novel support for PTSD-related accelerated aging in DNAm and extend the evidence base of known DNAm age correlates to the domains of neural integrity and cognition.

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We examined how wide ranges in levels of risk factors for cerebrovascular disease are associated with thickness of the human cerebral cortex in 115 individuals ages 43-83 with no cerebrovascular or neurologic history. Cerebrovascular risk factors included blood pressure, cholesterol, body mass index, creatinine, and diabetes-related factors. Variables were submitted into a principal components analysis that confirmed four orthogonal factors (Blood Pressure, Cholesterol, Cholesterol/Metabolic and Glucose). T1-weighted MRI was used to create models of the cortex for calculation of regional cortical thickness. Increasing blood pressure factor scores were associated with numerous regions of reduced thickness. Increasing glucose scores were modestly associated with areas of regionally decreased thickness. Increasing cholesterol scores, in contrast, were associated with thicker cortex across the whole brain. All findings were primarily independent of age. These results provide evidence that normal and moderately abnormal levels of parameters used to assess cerebrovascular health may impact brain structure, even in the absence of cerebrovascular disease. Our data have important implications for the clinical management of vascular health, as well as for what is currently conceptualized as "normal aging" as they suggest that subclinical levels of risk may impact cortical gray matter before a disease process is evident.