Dopamine Genetic Risk Score Predicts Depressive Symptoms in Healthy Adults and Adults with Depression

Background: Depression is a common source of human disability for which etiologic insights remain limited. Although abnormalities of monoamine neurotransmission, including dopamine, are theorized to contribute to the pathophysiology of depression, evidence linking dopamine-related genes to depression has been mixed. The current study sought to address this knowledge-gap by examining whether the combined effect of dopamine polymorphisms was associated with depressive symptomatology in both healthy individuals and individuals with depression. Methods: Data were drawn from three independent samples: (1) a discovery sample of healthy adult participants (n = 273); (2) a replication sample of adults with depression (n = 1,267); and (3) a replication sample of healthy adult participants (n = 382). A genetic risk score was created by combining functional polymorphisms from five genes involved in synaptic dopamine availability (COMT and DAT) and dopamine receptor binding (DRD1, DRD2, DRD3). Results: In the discovery sample, the genetic risk score was associated with depressive symptomatology (β = −0.80, p = 0.003), with lower dopamine genetic risk scores (indicating lower dopaminergic neurotransmission) predicting higher levels of depression. This result was replicated with a similar genetic risk score based on imputed genetic data from adults with depression (β = −0.51, p = 0.04). Results were of similar magnitude and in the expected direction in a cohort of healthy adult participants (β = −0.86, p = 0.15). Conclusions: Sequence variation in multiple genes regulating dopamine neurotransmission may influence depressive symptoms, in a manner that appears to be additive. Further studies are required to confirm the role of genetic variation in dopamine metabolism and depression

The Swift X-ray flaring afterglow of GRB 050607

The unique capability of the Swift satellite to perform a prompt and autonomous slew to a newly detected Gamma-Ray Burst (GRB) has yielded the discovery of interesting new properties of GRB X-ray afterglows, such as the steep early lightcurve decay and the frequent presence of flares detected up to a few hours after the GRB trigger. We present observations of GRB 050607, the fourth case of a GRB discovered by Swift with flares superimposed on the overall fading X-ray afterglow. The flares of GRB 050607 were not symmetric as in previously reported cases, showing a very steep rise and a shallower decay, similar to the Fast Rise, Exponential Decay that are frequently observed in the gamma-ray prompt emission. The brighter flare had a flux increase by a factor of approximately 25,peaking for 30 seconds at a count rate of approximately 30 counts s-1, and it presented hints of addition short time scale activity during the decay phase. There is evidence of spectral evolution during the flares. In particular, at the onset of the flares the observed emission was harder, with a gradual softening as each flare decayed. The very short time scale and the spectral variability during the flaring activity are indicators of possible extended periods of energy emission by the GRB central engine. The flares were followed by a phase of shallow decay, during which the forward shock was being refreshed by a long-lived central engine or by shells of lower Lorentz factors, and by a steepening after approximately 12 ks to a decay slope considered typical of X-ray afterglows.Comment: 23 pages, 5 figures, Accepted by the Astrophysical Journa

Genetic architecture of white matter hyperintensities differs in hypertensive and nonhypertensive ischemic stroke.

BACKGROUND AND PURPOSE: Epidemiological studies suggest that white matter hyperintensities (WMH) are extremely heritable, but the underlying genetic variants are largely unknown. Pathophysiological heterogeneity is known to reduce the power of genome-wide association studies (GWAS). Hypertensive and nonhypertensive individuals with WMH might have different underlying pathologies. We used GWAS data to calculate the variance in WMH volume (WMHV) explained by common single nucleotide polymorphisms (SNPs) as a measure of heritability (SNP heritability [HSNP]) and tested the hypothesis that WMH heritability differs between hypertensive and nonhypertensive individuals. METHODS: WMHV was measured on MRI in the stroke-free cerebral hemisphere of 2336 ischemic stroke cases with GWAS data. After adjustment for age and intracranial volume, we determined which cardiovascular risk factors were independent predictors of WMHV. Using the genome-wide complex trait analysis tool to estimate HSNP for WMHV overall and within subgroups stratified by risk factors found to be significant in multivariate analyses. RESULTS: A significant proportion of the variance of WMHV was attributable to common SNPs after adjustment for significant risk factors (HSNP=0.23; P=0.0026). HSNP estimates were higher among hypertensive individuals (HSNP=0.45; P=7.99×10(-5)); this increase was greater than expected by chance (P=0.012). In contrast, estimates were lower, and nonsignificant, in nonhypertensive individuals (HSNP=0.13; P=0.13). CONCLUSIONS: A quarter of variance is attributable to common SNPs, but this estimate was greater in hypertensive individuals. These findings suggest that the genetic architecture of WMH in ischemic stroke differs between hypertensives and nonhypertensives. Future WMHV GWAS studies may gain power by accounting for this interaction

Fermi Large Area Telescope View of the Core of the Radio Galaxy Centaurus A

We present gamma-ray observations with the LAT on board the Fermi Gamma-Ray Telescope of the nearby radio galaxy Centaurus~A. The previous EGRET detection is confirmed, and the localization is improved using data from the first 10 months of Fermi science operation. In previous work, we presented the detection of the lobes by the LAT; in this work, we concentrate on the gamma-ray core of Cen~A. Flux levels as seen by the LAT are not significantly different from that found by EGRET, nor is the extremely soft LAT spectrum (\G=2.67\pm0.10_{stat}\pm0.08_{sys} where the photon flux is \Phi\propto E^{-\G}). The LAT core spectrum, extrapolated to higher energies, is marginally consistent with the non-simultaneous HESS spectrum of the source. The LAT observations are complemented by simultaneous observations from Suzaku, the Swift Burst Alert Telescope and X-ray Telescope, and radio observations with the Tracking Active Galactic Nuclei with Austral Milliarcsecond Interferometry (TANAMI) program, along with a variety of non-simultaneous archival data from a variety of instruments and wavelengths to produce a spectral energy distribution (SED). We fit this broadband data set with a single-zone synchrotron/synchrotron self-Compton model, which describes the radio through GeV emission well, but fails to account for the non-simultaneous higher energy TeV emission observed by HESS from 2004-2008. The fit requires a low Doppler factor, in contrast to BL Lacs which generally require larger values to fit their broadband SEDs. This indicates the \g-ray emission originates from a slower region than that from BL Lacs, consistent with previous modeling results from Cen~A. This slower region could be a slower moving layer around a fast spine, or a slower region farther out from the black hole in a decelerating flow.Comment: Accepted by ApJ. 32 pages, 5 figures, 2 tables. J. Finke and Y. Fukazawa corresponding author

Radiomic markers of intracerebral hemorrhage expansion on non-contrast CT: independent validation and comparison with visual markers

ObjectiveTo devise and validate radiomic signatures of impending hematoma expansion (HE) based on admission non-contrast head computed tomography (CT) of patients with intracerebral hemorrhage (ICH).MethodsUtilizing a large multicentric clinical trial dataset of hypertensive patients with spontaneous supratentorial ICH, we developed signatures predictive of HE in a discovery cohort (n = 449) and confirmed their performance in an independent validation cohort (n = 448). In addition to n = 1,130 radiomic features, n = 6 clinical variables associated with HE, n = 8 previously defined visual markers of HE, the BAT score, and combinations thereof served as candidate variable sets for signatures. The area under the receiver operating characteristic curve (AUC) quantified signatures’ performance.ResultsA signature combining select radiomic features and clinical variables attained the highest AUC (95% confidence interval) of 0.67 (0.61–0.72) and 0.64 (0.59–0.70) in the discovery and independent validation cohort, respectively, significantly outperforming the clinical (pdiscovery = 0.02, pvalidation = 0.01) and visual signature (pdiscovery = 0.03, pvalidation = 0.01) as well as the BAT score (pdiscovery < 0.001, pvalidation < 0.001). Adding visual markers to radiomic features failed to improve prediction performance. All signatures were significantly (p < 0.001) correlated with functional outcome at 3-months, underlining their prognostic relevance.ConclusionRadiomic features of ICH on admission non-contrast head CT can predict impending HE with stable generalizability; and combining radiomic with clinical predictors yielded the highest predictive value. By enabling selective anti-expansion treatment of patients at elevated risk of HE in future clinical trials, the proposed markers may increase therapeutic efficacy, and ultimately improve outcomes

Study of the reaction e^{+}e^{-} -->J/psi\pi^{+}\pi^{-} via initial-state radiation at BaBar

We study the process $e^+e^-\to J/\psi\pi^{+}\pi^{-}$ with initial-state-radiation events produced at the PEP-II asymmetric-energy collider. The data were recorded with the BaBar detector at center-of-mass energies 10.58 and 10.54 GeV, and correspond to an integrated luminosity of 454 $\mathrm{fb^{-1}}$. We investigate the $J/\psi \pi^{+}\pi^{-}$ mass distribution in the region from 3.5 to 5.5 $\mathrm{GeV/c^{2}}$. Below 3.7 $\mathrm{GeV/c^{2}}$ the $\psi(2S)$ signal dominates, and above 4 $\mathrm{GeV/c^{2}}$ there is a significant peak due to the Y(4260). A fit to the data in the range 3.74 -- 5.50 $\mathrm{GeV/c^{2}}$ yields a mass value $4244 \pm 5$ (stat) $\pm 4$ (syst)$\mathrm{MeV/c^{2}}$ and a width value $114 ^{+16}_{-15}$ (stat)$\pm 7$(syst)$\mathrm{MeV}$ for this state. We do not confirm the report from the Belle collaboration of a broad structure at 4.01 $\mathrm{GeV/c^{2}}$. In addition, we investigate the $\pi^{+}\pi^{-}$ system which results from Y(4260) decay

Genetic overlap between diagnostic subtypes of ischemic stroke

Background and Purpose: Despite moderate heritability, the phenotypic heterogeneity of ischemic stroke has hampered gene discovery, motivating analyses of diagnostic subtypes with reduced sample sizes. We assessed evidence for a shared genetic basis among the 3 major subtypes: large artery atherosclerosis (LAA), cardioembolism, and small vessel disease (SVD), to inform potential cross-subtype analyses. Methods: Analyses used genome-wide summary data for 12 389 ischemic stroke cases (including 2167 LAA, 2405 cardioembolism, and 1854 SVD) and 62 004 controls from the Metastroke consortium. For 4561 cases and 7094 controls, individual-level genotype data were also available. Genetic correlations between subtypes were estimated using linear mixed models and polygenic profile scores. Meta-analysis of a combined LAA-SVD phenotype (4021 cases and 51 976 controls) was performed to identify shared risk alleles. Results: High genetic correlation was identified between LAA and SVD using linear mixed models (rg=0.96, SE=0.47, P=9×10-4) and profile scores (rg=0.72; 95% confid

COL4A2 is associated with lacunar ischemic stroke and deep ICH: Meta-analyses among 21,500 cases and 40,600 controls

Objective: To determine whether common variants in familial cerebral small vessel disease (SVD) genes confer risk of sporadic cerebral SVD. Methods: We meta-analyzed genotype data from individuals of European ancestry to determine associations of common single nucleotide polymorphisms (SNPs) in 6 familial cerebral SVD genes (COL4A1, COL4A2, NOTCH3, HTRA1, TREX1, and CECR1) with intracerebral hemorrhage (ICH) (deep, lobar, all; 1,878 cases, 2,830 controls) and ischemic stroke (IS) (lacunar, cardioembolic, large vessel disease, all; 19,569 cases, 37,853 controls). We applied data quality filters and set statistical significance thresholds accounting for linkage disequilibrium and multiple testing. Results: A locus in COL4A2 was associated (significance threshold p , 3.5 3 1024) with both lacunar IS (lead SNP rs9515201: odds ratio [OR] 1.17, 95%confidence interval [CI] 1.11-1.24, p 56.62 31028) and deep ICH (lead SNP rs4771674: OR 1.28, 95%CI 1.13-1.44, p 55.76 3 1025). A SNP in HTRA1 was associated (significance threshold p , 5.5 3 1024) with lacunar IS (rs79043147: OR 1.23, 95%CI 1.10-1.37, p 5 1.90 3 1024) and less robustly with deep ICH. There was no clear evidence for association of common variants in either COL4A2 or HTRA1 with non-SVD strokes or in any of the other genes with any stroke phenotype

Burden of Risk Alleles for Hypertension Increases Risk of Intracerebral Hemorrhage

Background and Purpose-Genetic variation influences risk of intracerebral hemorrhage (ICH). Hypertension (HTN) is a potent risk factor for ICH and several common genetic variants (single nucleotide polymorphisms [SNPs]) associated with blood pressure levels have been identified. We sought to determine whether the cumulative burden of blood pressure-related SNPs is associated with risk of ICH and pre-ICH diagnosis of HTN. Methods-We conducted a prospective multicenter case-control study in 2272 subjects of European ancestry (1025 cases and 1247 control subjects). Thirty-nine SNPs reported to be associated with blood pressure levels were identified from the National Human Genome Research Institute genomewide association study catalog. Single-SNP association analyses were performed for the outcomes ICH and pre-ICH HTN. Subsequently, weighted and unweighted genetic risk scores were constructed using these SNPs and entered as the independent variable in logistic regression models with ICH and pre-ICH HTN as the dependent variables. Results-No single SNP was associated with either ICH or pre-ICH HTN. The blood pressure-based unweighted genetic risk score was associated with risk of ICH (OR, 1.11; 95% CI, 1.02-1.21; P=0.01) and the subset of ICH in deep regions (OR, 1.18; 95% CI, 1.07-1.30; P=0.001), but not with the subset of lobar ICH. The score was associated with a history of HTN among control subjects (OR, 1.17; 95% CI, 1.04-1.31; P=0.009) and ICH cases (OR, 1.15; 95% CI, 1.01-1.31; P=0.04). Similar results were obtained when using a weighted score. Conclusion-Increasing numbers of high blood pressure-related alleles are associated with increased risk of deep ICH as well as with clinically identified HTN. (Stroke. 2012; 43: 2877-2883.

Genetic Variants in CETP Increase Risk of Intracerebral Hemorrhage

OBJECTIVE: In observational epidemiologic studies, higher plasma high-density lipoprotein cholesterol (HDL-C) has been associated with increased risk of intracerebral hemorrhage (ICH). DNA sequence variants that decrease cholesteryl ester transfer protein (CETP) gene activity increase plasma HDL-C; as such, medicines that inhibit CETP and raise HDL-C are in clinical development. Here, we test the hypothesis that CETP DNA sequence variants associated with higher HDL-C also increase risk for ICH.METHODS: We performed 2 candidate-gene analyses of CETP. First, we tested individual CETP variants in a discovery cohort of 1,149 ICH cases and 1,238 controls from 3 studies, followed by replication in 1,625 cases and 1,845 controls from 5 studies. Second, we constructed a genetic risk score comprised of 7 independent variants at the CETP locus and tested this score for association with HDL-C as well as ICH risk.RESULTS: Twelve variants within CETP demonstrated nominal association with ICH, with the strongest association at the rs173539 locus (odds ratio [OR] = 1.25, standard error [SE] = 0.06, p = 6.0 × 10(-4) ) with no heterogeneity across studies (I(2) = 0%). This association was replicated in patients of European ancestry (p = 0.03). A genetic score of CETP variants found to increase HDL-C by ∼2.85mg/dl in the Global Lipids Genetics Consortium was strongly associated with ICH risk (OR = 1.86, SE = 0.13, p = 1.39 × 10(-6) ).INTERPRETATION: Genetic variants in CETP associated with increased HDL-C raise the risk of ICH. Given ongoing therapeutic development in CETP inhibition and other HDL-raising strategies, further exploration of potential adverse cerebrovascular outcomes may be warranted. Ann Neurol 2016;80:730-740