[Show abstract][Hide abstract] ABSTRACT: IMPORTANCE We investigated the variation in neuropsychological function explained by risk alleles at the psychosis susceptibility gene ZNF804A and its interacting partners using single nucleotide polymorphisms (SNPs), polygenic scores, and epistatic analyses. Of particular importance was the relative contribution of the polygenic score vs epistasis in variation explained. OBJECTIVES To (1) assess the association between SNPs in ZNF804A and the ZNF804A polygenic score with measures of cognition in cases with psychosis and (2) assess whether epistasis within the ZNF804A pathway could explain additional variation above and beyond that explained by the polygenic score. DESIGN, SETTING, AND PARTICIPANTS Patients with psychosis (n = 424) were assessed in areas of cognitive ability impaired in schizophrenia including IQ, memory, attention, and social cognition. We used the Psychiatric GWAS Consortium 1 schizophrenia genome-wide association study to calculate a polygenic score based on identified risk variants within this genetic pathway. Cognitive measures significantly associated with the polygenic score were tested for an epistatic component using a training set (n = 170), which was used to develop linear regression models containing the polygenic score and 2-SNP interactions. The best-fitting models were tested for replication in 2 independent test sets of cases: (1) 170 individuals with schizophrenia or schizoaffective disorder and (2) 84 patients with broad psychosis (including bipolar disorder, major depressive disorder, and other psychosis). MAIN OUTCOMES AND MEASURES Participants completed a neuropsychological assessment battery designed to target the cognitive deficits of schizophrenia including general cognitive function, episodic memory, working memory, attentional control, and social cognition. RESULTS Higher polygenic scores were associated with poorer performance among patients on IQ, memory, and social cognition, explaining 1% to 3% of variation on these scores (range, P = .01 to .03). Using a narrow psychosis training set and independent test sets of narrow phenotype psychosis (schizophrenia and schizoaffective disorder), broad psychosis, and control participants (n = 89), the addition of 2 interaction terms containing 2 SNPs each increased the R2 for spatial working memory strategy in the independent psychosis test sets from 1.2% using the polygenic score only to 4.8% (P = .11 and .001, respectively) but did not explain additional variation in control participants. CONCLUSIONS AND RELEVANCE These data support a role for the ZNF804A pathway in IQ, memory, and social cognition in cases. Furthermore, we showed that epistasis increases the variation explained above the contribution of the polygenic score.
[Show abstract][Hide abstract] ABSTRACT: Schizophrenia is an idiopathic mental disorder with a heritable component and a substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases and 6,243 controls) followed by meta-analysis with previous schizophrenia GWAS (8,832 cases and 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls and 581 parent-offspring trios). We identified 22 loci associated at genome-wide significance; 13 of these are new, and 1 was previously implicated in bipolar disorder. Examination of candidate genes at these loci suggests the involvement of neuronal calcium signaling. We estimate that 8,300 independent, mostly common SNPs (95% credible interval of 6,300-10,200 SNPs) contribute to risk for schizophrenia and that these collectively account for at least 32% of the variance in liability. Common genetic variation has an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this disorder.
[Show abstract][Hide abstract] ABSTRACT: Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease (CVD), range from 34 to 50%. Genetic variants so far identified by genome-wide association (GWA) studies only explain a small proportion (< 2%) of its variation.
We conducted a meta-analysis of 28 GWA studies, including more than 90,000 subjects of European ancestry, the first GWA meta-analysis of fibrinogen levels in 7 African Americans studies totaling 8,289 samples, and a GWA study in Hispanic-Americans totaling 1,366 samples. Evaluation for association of SNPs with clinical outcomes included a total of 40,695 cases and 85,582 controls for coronary artery disease (CAD), 4,752 cases and 24,030 controls for stroke, and 3,208 cases and 46,167 controls for venous thromboembolism (VTE). Overall, we identified 24 genome-wide significant (P<5x10(-8)) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the three structural fibrinogen genes and pathways related to inflammation, adipocytokines and thyrotrophin-releasing hormone signaling. Whereas lead SNPs in a few loci were significantly associated with CAD, the combined effect of all 24 fibrinogen-associated lead SNPs was not significant for CAD, stroke or VTE.
We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and CAD, stroke or VTE.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND AND PURPOSE: Recently, a novel locus at 17q25 was associated with white matter hyperintensities (WMH) on MRI in stroke-free individuals. We aimed to replicate the association with WMH volume (WMHV) in patients with ischemic stroke. If the association acts by promoting a small vessel arteriopathy, it might be expected to also associate with lacunar stroke. METHODS: We quantified WMH on MRI in the stroke-free hemisphere of 2588 ischemic stroke cases. Association between WMHV and 6 single-nucleotide polymorphisms at chromosome 17q25 was assessed by linear regression. These single-nucleotide polymorphisms were also investigated for association with lacunar stroke in 1854 cases and 51 939 stroke-free controls from METASTROKE. Meta-analyses with previous reports and a genetic risk score approach were applied to identify other novel WMHV risk variants and uncover shared genetic contributions to WMHV in community participants without stroke and ischemic stroke. RESULTS: Single-nucleotide polymorphisms at 17q25 were associated with WMHV in ischemic stroke, the most significant being rs9894383 (P=0.0006). In contrast, there was no association between any single-nucleotide polymorphism and lacunar stroke. A genetic risk score analysis revealed further genetic components to WMHV shared between community participants without stroke and ischemic stroke. CONCLUSIONS: This study provides support for an association between the 17q25 locus and WMH. In contrast, it is not associated with lacunar stroke, suggesting that the association does not act by promoting small-vessel arteriopathy or the same arteriopathy responsible for lacunar infarction.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Short course of dual antiplatelet therapy for early secondary prevention is a promising treatment for patients with minor stroke or transient ischemic attack at high risk of recurrence. METHODS: We examined the efficacy and safety of dual antiplatelets in patients with transient ischemic attack or minor stroke, defined as National Institute of Health Stroke Scale scores 0-3, in a subgroup analysis of Clopidogrel plus aspirin versus Aspirin alone for Reducing embolization in patients with acute symptomatic cerebral or carotid artery stenosis (CLAIR) study. Microembolic signals on transcranial Doppler monitoring was used as surrogate marker for recurrent stroke risk. Patients with ≥1 microembolic signals at baseline were randomized to receive dual therapy (aspirin 75-160 mg daily and clopidogrel 300 mg day 1 then 75 mg daily) or monotherapy (aspirin 75-160 mg daily) for seven-days. RESULTS: Sixty-five of 100 patients recruited had transient ischemic attack or minor stroke: 30 received dual therapy and 35 received monotherapy. Mean onset-to-randomization was 2·3 days in dual therapy group and 3·2 days in monotherapy group (P = 0·03). At day 7, the proportion of patients with ≥1 microembolic signals was 9 of 29 patients in dual therapy group and 18 of 34 patients in monotherapy group (adjusted relative risk reduction 41·4%, 95% CI 29·8-51·1, P < 0·001). The median number of microembolic signals on day 7 was 0 in dual therapy group and 1·0 in monotherapy group (P = 0·046). No patients had intracranial or severe systemic hemorrhage. CONCLUSIONS: Early dual therapy with clopidogrel and aspirin reduces microembolic signals in patients with minor ischemic stroke or transient ischemic attack, without causing significant bleeding complications.
International Journal of Stroke 03/2013; · 4.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND AND PURPOSE: Recent evidence suggests current best medical treatment may be sufficient to prevent stroke in patients with asymptomatic carotid stenosis. If this is the case, then it is important to determine risk reduction provided by treatments. Using Asymptomatic Carotid Emboli Study (ACES) prospective data, the effect of current treatment and risk factors on future stroke and transient ischemic attack risk were determined. METHODS: Four-hundred seventy-seven patients with asymptomatic carotid stenosis were followed-up every 6 months for 2 years. Changes in risk factors and stroke prevention therapies were reviewed at each visit. Using time-dependent Cox regression, the relationship between current treatment over time was determined and presented as hazard ratios and 95% confidence intervals for risk of stroke, transient ischemic attack, and cardiovascular death end points. RESULTS: On multivariate analysis, antiplatelets (P=0.001) and lower mean blood pressure (P=0.002) were independent predictors of reduced risk of ipsilateral stroke and transient ischemic attack. Antiplatelets (P<0.0001) and antihypertensives (P<0.0001) were independent predictors of a lower risk of any stroke or cardiovascular death. CONCLUSIONS: Antiplatelet therapy and blood pressure control are the most important factors in reducing short-term stroke and cardiovascular risk in patients with asymptomatic carotid stenosis. More prospective data are required for medical treatments in asymptomatic carotid stenosis in particular for current statin usage.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND:Adequate control of blood pressure reduces the risk of recurrent stroke. We conducted a randomized controlled study to determine whether home blood pressure monitoring with nurse-led telephone support would reduce blood pressure in patients with hypertension and a history of stroke. METHODS:We recruited 381 participants (mean age 72 years) from outpatient and inpatient stroke clinics between Mar. 1, 2007, and Aug. 31, 2009. Nearly half (45%, 170) of the participants had some disability due to stroke. Participants were visited at home for a baseline assessment and randomly allocated to home blood pressure monitoring (n = 187) or usual care (n = 194). Those in the intervention group were given a monitor, brief training and telephone support. Participants who had home blood pressure readings consistently over target (target < 130/80 mm Hg) were advised to consult their family physician. The main outcome measure was a fall in systolic blood pressure after 12 months, measured by an independent researcher unaware of group allocation. RESULTS:Despite more patients in the intervention group than in the control group having changes to antihypertensive treatment during the trial period (60.1% [98/163] v. 47.6% [78/164], p = 0.02), the fall in systolic blood pressure from baseline did not differ significantly between the groups (adjusted mean difference 0.3 mm Hg, 95% confidence interval -3.6 to 4.2 mm Hg). Subgroup analysis showed significant interaction with disability due to stroke (p = 0.03 at 6 months) and baseline blood pressure (p = 0.03 at 12 months). INTERPRETATION:Overall, home monitoring did not improve blood pressure control in patients with hypertension and a history of stroke. It was associated with a fall in systolic pressure in patients who had uncontrolled blood pressure at baseline and those without disability due to stroke. Trial registration: ClinicalTrials.gov registration NCT00514800.
Canadian Medical Association Journal 11/2012; · 6.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Epidemiological evidence supports a genetic predisposition to stroke. Recent advances, primarily using the genome wide association study approach, are transforming what we know about the genetics of multifactorial stroke and are identifying novel stroke genes. Current findings are consistent with different stroke subtypes having different genetic architecture. These discoveries may identify novel pathways involved in stroke pathogenesis, and suggest new treatment approaches. However the already identified genetic variants explain only a small proportion of overall stroke risk and therefore are not currently useful in predicting risk in the individual patient. This may become a reality as we identify a greater number of stroke risk variants which explain the majority of genetic risk, and perhaps when information on rare variants, identified by whole genome sequencing, is also incorporated into risk algorithms. Pharmacogenomics may offer the potential for earlier implementation of "personalized genetic " medicine. Genetic variants affecting clopidogrel and warfarin metabolism may identify non-responders and reduce side effects, but these approaches have not yet been widely adopted in clinical practice.
BMC Medicine 09/2012; 10(1):113. · 7.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Barrett's esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia, and it strongly predisposes to esophageal adenocarcinoma (EAC), a tumor with a very poor prognosis. We report the first genome-wide association study on Barrett's esophagus, comprising ,852 UK cases and 5,72 UK controls in the discovery stage and 5,986 cases and 2,825 controls in the replication stage. Variants at two loci were associated with disease risk: chromosome 6p2, rs9257809 (P combined = 4.09 × 0 −9 ; odds ratio (OR) = .2, 95% confidence interval (CI) =.3–.28), within the major histocompatibility complex locus, and chromosome 6q24, rs9936833 (P combined = 2.74 × 0 −0 ; OR = .4, 95% CI = .0–.9), for which the closest protein-coding gene is FOXF1, which is implicated in esophageal development and structure. We found evidence that many common variants of small effect contribute to genetic susceptibility to Barrett's esophagus and that SNP alleles predisposing to obesity also increase risk for Barrett's esophagus. Barrett's esophagus is one of the most common premalignant lesions in the western world. It affects over 2% of the adult population and, unlike bowel polyps, lacks any proven effective therapy 1 . In the major-ity of cases, Barrett's esophagus is associated with chronic gastro-esophageal reflux disease (GERD), including esophagitis 2,3 . Over 80% of affected individuals have a hiatus hernia in the lower esophagus that facilitates the reflux of acid and bile into the esophagus 4 . The measured annual risk of EAC in individuals with Barrett's esophagus varies widely but is approximately 0.4–1% (refs. 5–7). Notably, the incidence of EAC has been rising by 3% each year for the last 30 years; it is now the fifth most common cancer in the UK 8 . Despite modern multimodality therapy, the prog-nosis for EAC remains poor, with a 9–15% 5-year survival rate 9,10 . The etiology of Barrett's esophagus is not well characterized. Environmental factors, such as diet, are weakly associated with GERD, Barrett's esophagus and EAC, and obesity is a known risk factor for all three conditions 11 . There is also evidence implicating genetic factors: relative risks are increased by 2-to 4-fold for GERD, Barrett's esophagus and EAC when one first-degree relative is affected 12–17 . A segregation analysis of 881 pedigrees of familial Barrett's esophagus supports an incompletely dominant inheritance model with a polygenic component 18 . Extensive candidate gene and linkage searches have to date been unsuccessful in identifying genetic variants that are associated with risk of Barrett's esophagus 19 . As part of the Wellcome Trust Case Control Consortium 2 (WTCCC2) study of 15 common disorders and traits, we present the results of the first genome-wide association study of Barrett's esophagus susceptibility. Using a discovery cohort from the UK (with case samples from the Aspirin and Esomeprazole Chemoprevention Trial of Cancer in Barrett's esophagus (AspECT)) 20 and five repli-cation cohorts (including case samples from CHemoprevention Of Premalignant Intestinal Neoplasia (ChOPIN) and Esophageal Adenocarcinoma GenEtics Consortium (EAGLE) studies 9,20), we identified two variants associated with Barrett's esophagus, each with combined evidence at P < 5 × 10 −8 . The analysis workflow is outlined in Supplementary Figure 1, and characteristics of the case and con-trol samples that were included can be found in the Online Methods and Supplementary Table 1. For the discovery analysis, cases with histologically confirmed Barrett's esophagus (Online Methods) were recruited from sites across the UK (Supplementary Table 2). Population controls were taken from the WTCCC2 common set of 1958 Birth Cohort (58C) and National Blood Service (UKBS) samples as previously described 21 .
[Show abstract][Hide abstract] ABSTRACT: Better methods are required to identify patients with asymptomatic carotid stenosis (ACS) at risk of future stroke. Two potential markers of high risk are echolucent plaque morphology on carotid ultrasound and embolic signals (ES) in the ipsilateral middle cerebral artery on transcranial Doppler ultrasound (TCD). We explored the predictive value of a score based on these 2 measures in the prospective, observational, international multicenter Asymptomatic Carotid Emboli Study.
A total of 435 recruited subjects with ACS ≥70% had baseline ultrasound images and TCD data available. Subjects were prospectively followed up for 2 years.
A total of 164 (37.7%) plaques were graded as echolucent. Plaque echolucency at baseline was associated with an increased risk of ipsilateral stroke alone (hazard ratio [HR] 6.43, 95% confidence interval [CI] 1.36-30.44, p = 0.019). A combined variable of plaque echolucency and ES positivity at baseline was associated with a markedly increased risk of ipsilateral stroke alone (HR 10.61, 95% CI 2.98-37.82, p = 0.0003). This association remained significant after controlling for risk factors, degree of carotid stenosis, and antiplatelet medication.
Plaque morphology assessed using a simple, and clinically applicable, visual rating scale predicts ipsilateral stroke risk in ACS. The combination of ES detection and plaque morphology allows a greater prediction than either measure alone and identifies a high-risk group with an annual stroke risk of 8%, and a low-risk group with a risk of <1% per annum. This risk stratification may prove useful in the selection of patients with ACS for endarterectomy.
[Show abstract][Hide abstract] ABSTRACT: Stroke represents an enormous health problem worldwide. It describes a clinical syndrome which can be caused by a number of different pathologies, rather than a single disease. Over 80% of strokes are ischaemic, as opposed to haemorrhagic. This review covers advances in the genetics of both monogenic and multifactorial ischaemic stroke. Like many other complex diseases, progress in identifying genes for multifactorial stroke has been disappointing. However, genome-wide association study (GWAS) technology is starting to have a major impact on our understanding of the genetics of stroke. Early studies have shown that genetic associations identified with other diseases known to be associated with stroke, such as coronary heart disease and atrial fibrillation, are themselves genetic risk factors for stroke. A number of stroke GWASs are nearing completion; these have identified novel associations with ischaemic stroke. Most associations reported to date are with specific stroke subtypes. This parallels findings from monogenic causes of stroke where individual mutations usually predispose to specific stroke subtypes. This has implications for the understanding of the pathogenesis of stroke, and emphasizes the importance of careful stroke subtyping in genetic epidemiology studies. So far, studies have looked for genetic risk factors for stroke acting independently of environmental factors. However, we know that conventional environmental risk factors are important in stroke pathogenesis, and considerable evidence suggests that gene-environment interactions will be important. Identifying these is likely to require much larger sample sizes.
Human Molecular Genetics 08/2011; 20(R2):R124-31. · 7.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Improved methods are required to identify patients with asymptomatic carotid stenosis at high risk for stroke. The Asymptomatic Carotid Emboli Study recently showed embolic signals (ES) detected by transcranial Doppler on 2 recordings that lasted 1-hour independently predict 2-year stroke risk. ES detection is time-consuming, and whether similar predictive information could be obtained from simpler recording protocols is unknown.
In a predefined secondary analysis of Asymptomatic Carotid Emboli Study, we looked at the temporal variation of ES. We determined the predictive yield associated with different recording protocols and with the use of a higher threshold to indicate increased risk (≥2 ES). To compare the different recording protocols, sensitivity and specificity analyses were performed using analysis of receiver-operator characteristic curves.
Of 477 patients, 467 had baseline recordings adequate for analysis; 77 of these had ES on 1 or both of the 2 recordings. ES status on the 2 recordings was significantly associated (P<0.0001), but there was poor agreement between ES positivity on the 2 recordings (κ=0.266). For the primary outcome of ipsilateral stroke or transient ischemic attack, the use of 2 baseline recordings lasting 1 hour had greater predictive accuracy than either the first baseline recording alone (P=0.0005), a single 30-minute (P<0.0001) recording, or 2 recordings lasting 30 minutes (P<0.0001). For the outcome of ipsilateral stroke alone, two recordings lasting 1 hour had greater predictive accuracy when compared to all other recording protocols (all P<0.0001).
Our analysis demonstrates the relative predictive yield of different recording protocols that can be used in application of the technique in clinical practice. Two baseline recordings lasting 1 hour as used in Asymptomatic Carotid Emboli Study gave the best risk prediction.
[Show abstract][Hide abstract] ABSTRACT: Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
[Show abstract][Hide abstract] ABSTRACT: Up to 50% of patients with acute stroke are taking antihypertensive drugs on hospital admission. However, whether such treatment should be continued during the immediate post-stroke period is unclear. We therefore aimed to assess the efficacy and safety of continuing or stopping pre-existing antihypertensive drugs in patients who had recently had a stroke.
The Continue or Stop Post-Stroke Antihypertensives Collaborative Study (COSSACS) was a UK multicentre, prospective, randomised, open, blinded-endpoint trial. Patients were recruited at 49 UK National Institute for Health Research Stroke Research Network centres from January 1, 2003, to March 31, 2009. Patients aged over 18 years who were taking antihypertensive drugs were enrolled within 48 h of stroke and the last dose of antihypertensive drug. Patients were randomly assigned (1:1) by secure internet central randomisation to either continue or stop pre-existing antihypertensive drugs for 2 weeks. Patients and clinicians who randomly assigned patients were unmasked to group allocation. Clinicians who assessed 2-week outcomes and 6-month outcomes were masked to group allocation. The primary endpoint was death or dependency at 2 weeks, with dependency defined as a modified Rankin scale score greater than 3 points. Analysis was by intention to treat. This trial is registered with the International Standard Randomised Controlled Trial Register, number ISRCTN89712435.
763 patients were assigned to continue (n=379) or stop (n=384) pre-existing antihypertensive drugs. 72 of 379 patients in the continue group and 82 of 384 patients in the stop group reached the primary endpoint (relative risk 0.86, 95% CI 0.65-1.14; p=0.3). The difference in systolic blood pressure at 2 weeks between the continue group and the stop group was 13 mm Hg (95% CI 10-17) and the difference in diastolic blood pressure was 8 mm Hg (6-10; difference between groups p<0.0001). No substantial differences were observed between groups in rates of serious adverse events, 6-month mortality, or major cardiovascular events.
Continuation of antihypertensive drugs did not reduce 2-week death or dependency, cardiovascular event rate, or mortality at 6 months. Lower blood pressure levels in those who continued antihypertensive treatment after acute mild stroke were not associated with an increase in adverse events. These neutral results might be because COSSACS was underpowered owing to early termination of the trial, and support the continuation of ongoing research trials.
The Health Foundation and The Stroke Association.
The Lancet Neurology 08/2010; 9(8):767-75. · 23.92 Impact Factor