The advantages of UK Biobank's open-access strategy for health research.

Ready access to health research studies is becoming more important as researchers, and their funders, seek to maximize the opportunities for scientific innovation and health improvements. Large-scale population-based prospective studies are particularly useful for multidisciplinary research into the causes, treatment and prevention of many different diseases. UK Biobank has been established as an open-access resource for public health research, with the intention of making the data as widely available as possible in an equitable and transparent manner. Access to UK Biobank's unique breadth of phenotypic and genetic data has attracted researchers worldwide from across academia and industry. As a consequence, it has enabled scientists to perform world-leading collaborative research. Moreover, open access to an already deeply characterized cohort has encouraged both public and private sector investment in further enhancements to make UK Biobank an unparalleled resource for public health research and an exemplar for the development of open-access approaches for other studies.

Shared genetic aetiology between cognitive functions and physical and mental health in UK Biobank (N=112 151) and 24 GWAS consortia.

Causes of the well-documented association between low levels of cognitive functioning and many adverse neuropsychiatric outcomes, poorer physical health and earlier death remain unknown. We used linkage disequilibrium regression and polygenic profile scoring to test for shared genetic aetiology between cognitive functions and neuropsychiatric disorders and physical health. Using information provided by many published genome-wide association study consortia, we created polygenic profile scores for 24 vascular-metabolic, neuropsychiatric, physiological-anthropometric and cognitive traits in the participants of UK Biobank, a very large population-based sample (N=112 151). Pleiotropy between cognitive and health traits was quantified by deriving genetic correlations using summary genome-wide association study statistics and to the method of linkage disequilibrium score regression. Substantial and significant genetic correlations were observed between cognitive test scores in the UK Biobank sample and many of the mental and physical health-related traits and disorders assessed here. In addition, highly significant associations were observed between the cognitive test scores in the UK Biobank sample and many polygenic profile scores, including coronary artery disease, stroke, Alzheimer's disease, schizophrenia, autism, major depressive disorder, body mass index, intracranial volume, infant head circumference and childhood cognitive ability. Where disease diagnosis was available for UK Biobank participants, we were able to show that these results were not confounded by those who had the relevant disease. These findings indicate that a substantial level of pleiotropy exists between cognitive abilities and many human mental and physical health disorders and traits and that it can be used to predict phenotypic variance across samples.

Genetic associations with brain microbleeds: Systematic review and meta-analyses.

OBJECTIVE: We performed a systematic review and meta-analyses to assess the evidence for genetic associations with brain microbleeds (BMBs). METHODS: We sought all published studies of the association between any genetic polymorphism and BMBs studied in a total of >100 people. We critically appraised studies, and calculated pooled odds ratios (ORs) using the generic inverse variance fixed effects method. We used I² and χ² statistics to assess heterogeneity, and fail-safe N estimates to assess the robustness of our results. RESULTS: Only the APOE ε2/3/4 polymorphism had been studied in >100 people (10 studies, 7,351 participants). Compared with people with the ε3/ε3 genotype, carriers of the ε4 allele (ε4+) were statistically significantly more likely to have BMBs in any location (ε4+ vs ε3/ε3: pooled OR 1.22, 95% confidence interval [CI] 1.05-1.41, p = 0.01). For strictly lobar BMBs, this association appeared slightly stronger (ε4+ vs ε3/ε3: pooled OR 1.35, 95% CI 1.10-1.66, p = 0.005). The association of ε4+ genotypes with strictly lobar BMBs was reasonably robust to potential publication and reporting biases. CONCLUSIONS: Given the known associations of APOE alleles with lobar intracerebral hemorrhage and cerebral amyloid angiopathy, these findings support the concept that strictly lobar BMBs may be an imaging biomarker of cerebral amyloid angiopathy.

Cerebral small vessel endothelial structural changes predate hypertension in stroke-prone spontaneously hypertensive rats: a blinded, controlled immunohistochemical study of 5- to 21-week-old rats.

AIMS: The spontaneously hypertensive stroke-prone rat (SHRSP) is a potential animal model of human lacunar stroke, but there is little information on SHRSP small vessel pathology, especially in young rats. We investigated the structural changes that occur in cortical and subcortical vessels and adjacent tissue in SHRSP before, during and after the onset of hypertension. METHODS: We examined brains from SHRSP and Wistar Kyoto rats (WKY) at 5, 16 and 21 weeks of age. Structural changes in small arterioles and adjacent tissue were studied using antibodies to investigate different components of the neurovascular unit. We quantified staining in three standard regions, at two coronal levels. RESULTS: Immunostaining for claudin-5, a marker of endothelial tight junctions, was reduced in SHRSP at all ages compared to age-matched WKY controls. Smooth muscle actin, glial fibrillary acidic protein and ionized calcium-binding adaptor molecule 1 were increased in SHRSP vs. WKY by 16 weeks. Additionally, 21-week-old WKY and SHRSP rats fed a high-salt diet showed differences in claudin-5, glial fibrillary acidic protein and matrix metalloproteinase 9 staining compared to those fed a normal diet. CONCLUSION: Endothelial tight junction alterations of SHRSP rats from the earliest ages point towards increased susceptibility to blood-brain barrier dysfunction and stroke, which is exacerbated by salt loading. Salt loading may also damage the neurovascular unit in WKY controls.

Effects of apolipoprotein E genotype on outcome after ischaemic stroke, intracerebral haemorrhage and subarachnoid haemorrhage.

BACKGROUND: Rodent models of acute ischaemic stroke and head injury suggest that apolipoprotein E (APOE) genotype influences neuronal repair, regeneration and survival after brain injury. Possession of an APOE epsilon4 allele is associated with poor outcome after head injury in clinical studies. APOE might therefore influence outcome after acute stroke in humans. OBJECTIVE AND METHODS: To comprehensively search, identify, assess and carry out meta-analyses of studies reporting on the association between APOE and the combined outcome of death or dependency, or death alone, several months after ischaemic stroke, intracerebral haemorrhage (ICH) or subarachnoid haemorrhage (SAH). RESULTS: Main analyses included data from nine studies on 2262 patients (1453 with ischaemic stroke, 199 with ICH and 610 with SAH). Overall, epsilon4+ genotypes were not significantly associated with risk of death or dependency several months after stroke. However, there was significant heterogeneity between studies, and between the three pathological types of stroke. Epsilon4+ genotypes were associated with increased death or dependency after SAH (relative risk (RR) 1.40, 95% confidence interval (CI) 1.06 to 1.84), with a trend towards a similar association with ICH (RR 1.38, 95% CI 0.99 to 1.92), but not with ischaemic stroke (RR 0.98, 95% CI 0.85 to 1.12). Results were similar for death alone. CONCLUSIONS: APOE may differentially affect outcome after the three main pathological types of stroke. Further, large studies are needed to confirm or refute these findings, and to assess the possibility of an interaction between the effects of APOE and age.

Is hypertension a more frequent risk factor for deep than for lobar supratentorial intracerebral haemorrhage?

OBJECTIVE: To determine whether evidence from observational studies supports the widely held belief that hypertension is more commonly a risk factor for deep than for lobar supratentorial intracerebral haemorrhage. METHODS: Studies comparing the frequency of hypertension as a risk factor for deep versus lobar supratentorial intracerebral haemorrhage, excluding haemorrhages with identified secondary causes, were identified and subjected to a meta-analysis. The effects of predefined methodological quality criteria on the results were assessed and other sources of bias were considered. RESULTS: The pooled result from all 28 included studies (about 4000 patients) found hypertension to be about twice as common in patients with deep as in those with lobar haemorrhage (odds ratio (OR) 2.10, 95% confidence interval (95% CI) 1.82 to 2.42), but there was significant heterogeneity between studies. The pooled OR was less extreme for studies that used a pre-stroke definition of hypertension, were population based or included first-ever strokes only. In the three studies meeting all criteria (601 patients), deep haemorrhage was associated with a smaller, statistically significant excess of hypertension (OR 1.50, 95% CI 1.09 to 2.07). The OR for studies confined to younger patients seemed to be more extreme (12.32, 95% CI 6.13 to 24.77), but none of these studies fulfilled our methodological quality criteria. Additional, unquantified sources of bias included uncertainty about whether those doctors reporting brain scans were blind to hypertension status, uncertain reliability of the classification of haemorrhage location and variable rates of investigation for secondary causes. CONCLUSIONS: An excess of hypertension was found in patients with deep versus lobar intracerebral haemorrhages without an identified secondary cause, but this may be due to residual, unquantified methodological biases.