Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke.

Genetic factors have been implicated in stroke risk, but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls. We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus. We identified a new association for large vessel stroke within HDAC9 (encoding histone deacetylase 9) on chromosome 7p21.1 (including further replication in an additional 735 affected individuals and 28,583 controls) (rs11984041; combined P = 1.87 × 10(-11); odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.28-1.57). All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype. This suggests distinct genetic architectures for different stroke subtypes.

Sequence variants on chromosome 9p21.3 confer risk for atherosclerotic stroke.

OBJECTIVE: Recent studies have identified a major locus for risk for coronary artery disease and myocardial infarction on chromosome 9p21.3. Stroke, in particular, ischemic stroke caused by atherosclerotic disease, shares common mechanisms with myocardial infarction. We investigated whether the 9p21 region contributes to ischemic stroke risk. METHODS: In an initial screen, 15 single nucleotide polymorphisms (SNPs) covering the critical genetic interval on 9p21 were genotyped in samples from Southern Germany (1,090 cases, 1,244 control subjects) and the United Kingdom (758 cases, 872 control subjects, 3 SNPs). SNPs significantly associated with ischemic stroke or individual stroke subtypes in either of the screening samples were subsequently genotyped in 2,528 additional cases and 2,189 additional control subjects from Europe and North America. RESULTS: Genotyping of the screening samples demonstrated associations between seven SNPs and atherosclerotic stroke (all p < 0.05). Analysis of the full sample confirmed associations between six SNPs and atherosclerotic stroke in multivariate analyses controlling for demographic variables, coronary artery disease, myocardial infarction, and vascular risk factors (all p < 0.05). The odds ratios for the lead SNP (rs1537378-C) were similar in the various subsamples with a pooled odds ratio of 1.21 (95% confidence interval, 1.07-1.37) under both fixed- and random-effects models (p = 0.002). The point estimate for the population attributable risk is 20.1% for atherosclerotic stroke. INTERPRETATION: The chromosome 9p21.3 region represents a major risk locus for atherosclerotic stroke. The effect of this locus on stroke appears to be independent of its relation to coronary artery disease and other stroke risk factors. Our findings support a broad role of the 9p21 region in arterial disease.

Community-based stroke incidence in a Scottish population: the Scottish Borders Stroke Study.

BACKGROUND AND PURPOSE: The purpose of this study was to determine the incidence and case fatality of stroke in a geographically defined region of Scotland, a nation with a high cardiovascular risk. METHODS: All strokes occurring in residents of the Scottish Borders (population 106,352) were identified during a 24-month period from 1998 to 2000 using multiple overlapping methods of case-ascertainment. Standard criteria were used to define stroke and case fatality. Stroke subtypes were determined by computer tomography (CT) scan, MRI, or autopsy. RESULTS: 790 strokes were identified; 596 were first-ever-in-a-lifetime strokes (FES). 91.1% of FES underwent CT scan and/or autopsy. The crude annual incidence rate per 100,000 per year was: 280 (95% CI, 258 to 304) overall, 197 (95% CI 179-217) cerebral infarction, 24 (95% CI 17-31) intracerebral haemorrhage, 11 (95% CI 7-16) subarachnoid haemorrhage and 49 (95% CI 40-59) undetermined stroke. 28 day FES case fatality was 15.9% (95% CI, 13.2 to 19.1) increasing to 26.3% (95% CI, 23.0 to 30.0) at 1 year. Comparing 18 previous worldwide incidence studies with the SBSS showed a similar relative risk of stroke incidence and case fatality for FES and FES subtypes. CONCLUSIONS: The SBSS crude incidence rate is one of the highest in the world but age-adjusted rates, case fatality and relative risk for all stroke and stroke subtypes were not significantly different from the majority of previous studies. Unlike cardiovascular disease, the Scottish risk of stroke would appear to be similar to other populations worldwide.

Comparison of early and delayed respondents to a postal health survey: a questionnaire study of personality traits and neuropsychological symptoms.

Delayed response to a mail survey is related to age, lifestyle and socioeconomic status, and may provoke bias in epidemiological study. We investigated whether delayed respondents were associated with their personality traits and neuropsychological symptoms. Two hundred and ninety-eight painters from a Scottish dockyard cohort and their 571 male controls (general subjects) randomly recruited from the local residents completed a questionnaire, which included 24 statements of the Eysenck personality scales and 22 questions of neuropsychological symptoms. There was a similar distribution of delayed response between general subjects and painters, with a total of 55.6% early (returning questionnaires within 4 weeks), 33.4% intermediate (within 8 weeks) and 11.0% late respondents (after 8 weeks). The delayed response was related to only a few individual statements or symptoms, which varied between general subjects and painters. There were no significant differences in scores in statements of personality traits and neuropsychological symptoms among the three respondent groups, except for the late respondents in painters having an increased score of total neuropsychological symptoms at borderline significance. After adjustment for confounding the case-control analysis showed no significant association of the high scores of social conformity, neuroticism and symptoms with a delayed response. This study suggests that response to a postal health survey may not be influenced or biased by personality traits and neuropsychological symptoms.