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Objective: Anxiety disorders are common and often disabling. The goal of this study was to examine the genetic architecture of anxiety disorders and anxiety symptoms, which are also frequently comorbid with other mental disorders, such as major depressive disorder.Methods: Using one of the world's largest biobanks including genetic, environmental, and medical information, the Million Veteran Program, the authors performed a genome-wide association study (GWAS) of a continuous trait for anxiety (based on score on the Generalized Anxiety Disorder 2-item scale [GAD-2], N=199,611) as the primary analysis and selfreport of physician diagnosis of anxiety disorder (N=224,330) as a secondary analysis. Results:The authors identified five genome-wide significant signals for European Americans and one for African Americans on GAD-2 score. The strongest were on chromosome 3 (rs4603973) near SATB1, a global regulator of gene expression, and on chromosome 6 (rs6557168) near ESR1, which encodes an estrogen receptor. The locus identified on chromosome 7 (rs56226325, MAF=0.17) near MAD1L1 was previously identified in GWASs of bipolar disorder and schizophrenia. The authors replicated these findings in the summary statistics of two major published GWASs for anxiety, and also found evidence of significant genetic correlation between the GAD-2 score results and previous GWASs for anxiety (r g =0.75), depression (r g =0.81), and neuroticism (r g =0.75).Conclusions: This is the largest GWAS of anxiety traits to date. The authors identified novel genome-wide significant associations near genes involved with global regulation of gene expression (SATB1) and the estrogen receptor alpha (ESR1). Additionally, the authors identified a locus (MAD1L1) that may have implications for genetic vulnerability across several psychiatric disorders. This work provides new insights into genetic risk mechanisms underpinning anxiety and related psychiatric disorders.

Background Frailty is a key determinant of clinical outcomes. We sought to describe frailty among U.S. Veterans and its association with mortality. Methods Nationwide retrospective cohort study of regular Veterans Affairs (VA) users, aged at least 65 years in 2002–2012, followed through 2014, using national VA administrative and Medicare and Medicaid data. A frailty index (FI) for VA (VA-FI) was calculated using the cumulative deficit method. Thirty-one age-related deficits in health from diagnostic and procedure codes were included and were updated biennially. Survival analysis assessed associations between VA-FI and mortality. Results A VA-FI was calculated for 2,837,152 Veterans over 10 years. In 2002, 35.5% were non-frail (FI = 0–0.10), 32.6% were pre-frail (FI = 0.11–0.20), 18.9% were mildly frail (FI = 0.21–0.30), 8.7% were moderately frail (FI = 0.31–0.40), and 4.3% were severely frail (FI > 0.40). From 2002 to 2012, the prevalence of moderate frailty increased to 12.7%and severe frailty to 14.1%. Frailty was strongly associated with survival and was independent of age, sex, race, and smoking; the VA-FI better predicted mortality than age alone. Although prevalence of frailty rose over time, compared to non-frail Veterans, 2 years’ hazard ratios (95% confidence intervals) for mortality declined from a peak in 2004 of 2.01 (1.97–2.04), 3.49 (3.44–3.55), 5.88 (5.79–5.97), and 10.39 (10.23–10.56) for pre-frail, mildly, moderately, and severely frail, respectively, to 1.51 (1.49–1.53), 2.36 (2.33–2.39), 3.68 (3.63–3.73), 6.62 (6.53–6.71) in 2012. At every frailty level, risk of mortality was lower for women versus men and higher for blacks versus whites. Conclusions Frailty affects at least 3 of every 10 U.S. Veterans aged 65 years and older, and is strongly associated with mortality. The VA-FI could be used to more accurately estimate life expectancy and individualize care for Veterans.

We conducted genome-wide association analyses in over 250,000 participants of European and African ancestry from the Million Veteran Program using electronic health record-validated posttraumatic stress disorder (PTSD) diagnosis and quantitative symptom phenotypes. Applying genome-wide multiple testing correction, we identified three significant loci in European case-control analyses and 15 loci in quantitative symptom analyses. Genomic structural equation modeling indicated tight coherence of a PTSD symptom factor that shares genetic variance with a distinct internalizing (mood-anxiety-neuroticism) factor. Partitioned heritability indicated enrichment in several cortical and subcortical regions, and imputed genetically regulated gene expression in these regions was used to identify potential drug repositioning candidates. These results validate the biological coherence of the PTSD syndrome, inform its relationship to comorbid anxiety and depressive disorders, and provide new considerations for treatment.