Genetic Study of White Matter Integrity in UK Biobank (N=8448) and the Overlap With Stroke, Depression, and Dementia.

BACKGROUND AND PURPOSE: Structural integrity of the white matter is a marker of cerebral small vessel disease, which is the major cause of vascular dementia and a quarter of all strokes. Genetic studies provide a way to obtain novel insights in the disease mechanism underlying cerebral small vessel disease. The aim was to identify common variants associated with microstructural integrity of the white matter and to elucidate the relationships of white matter structural integrity with stroke, major depressive disorder, and Alzheimer disease. METHODS: This genome-wide association analysis included 8448 individuals from UK Biobank-a population-based cohort study that recruited individuals from across the United Kingdom between 2006 and 2010, aged 40 to 69 years. Microstructural integrity was measured as fractional anisotropy- (FA) and mean diffusivity (MD)-derived parameters on diffusion tensor images. White matter hyperintensity volumes (WMHV) were assessed on T2-weighted fluid-attenuated inversion recovery images. RESULTS: We identified 1 novel locus at genome-wide significance (VCAN [versican]: rs13164785; P=3.7×10-18 for MD and rs67827860; P=1.3×10-14 for FA). LD score regression showed a significant genome-wide correlation between FA, MD, and WMHV (FA-WMHV rG 0.39 [SE, 0.15]; MD-WMHV rG 0.56 [SE, 0.19]). In polygenic risk score analysis, FA, MD, and WMHV were significantly associated with lacunar stroke, MD with major depressive disorder, and WMHV with Alzheimer disease. CONCLUSIONS: Genetic variants within the VCAN gene may play a role in the mechanisms underlying microstructural integrity of the white matter in the brain measured as FA and MD. Mechanisms underlying white matter alterations are shared with cerebrovascular disease, and inherited differences in white matter microstructure impact on Alzheimer disease and major depressive disorder

Serum magnesium and calcium levels in relation to ischemic stroke

Objective: To determine whether serum magnesium and calcium concentrations are causally associated with ischemic stroke or any of its subtypes using the mendelian randomization approach. Methods: Analyses were conducted using summary statistics data for 13 single-nucleotide polymorphisms robustly associated with serum magnesium (n = 6) or serum calcium (n = 7) concentrations. The corresponding data for ischemic stroke were obtained from the MEGASTROKE consortium (34,217 cases and 404,630 noncases). Results: In standard mendelian randomization analysis, the odds ratios for each 0.1 mmol/L (about 1 SD) increase in genetically predicted serum magnesium concentrations were 0.78 (95% confidence interval [CI] 0.69–0.89; p = 1.3 × 10−4) for all ischemic stroke, 0.63 (95% CI 0.50–0.80; p = 1.6 × 10−4) for cardioembolic stroke, and 0.60 (95% CI 0.44–0.82; p = 0.001) for large artery stroke; there was no association with small vessel stroke (odds ratio 0.90, 95% CI 0.67–1.20; p = 0.46). Only the association with cardioembolic stroke was robust in sensitivity analyses. There was no association of genetically predicted serum calcium concentrations with all ischemic stroke (per 0.5 mg/dL [about 1 SD] increase in serum calcium: odds ratio 1.03, 95% CI 0.88–1.21) or with any subtype. Conclusions: This study found that genetically higher serum magnesium concentrations are associated with a reduced risk of cardioembolic stroke but found no significant association of genetically higher serum calcium concentrations with any ischemic stroke subtype

Exome array analysis of adverse reactions to fluoropyrimidine-based therapy for gastrointestinal cancer.

Fluoropyrimidines, including 5-fluororacil (5FU) and its pro-drug Capecitabine, are the common treatment for colorectal, breast, neck and head cancers-either as monotherapy or in combination therapy. Adverse reactions (ADRs) to the treatment are common and often result in treatment discontinuation or dose reduction. Factors contributing to ADRs, including genetic variation, are poorly characterized. We performed exome array analysis to identify genetic variants that contribute to adverse reactions. Our final dataset consisted of 504 European ancestry individuals undergoing fluoropyrimidine-based therapy for gastrointestinal cancer. A subset of 254 of these were treated with Capecitabine. All individuals were genotyped on the Illumina HumanExome Array. Firstly, we performed SNP and gene-level analyses of protein-altering variants on the array to identify novel associations the following ADRs, which were grouped into four phenotypes based on symptoms of diarrhea, mucositis, and neutropenia and hand-and-foot syndrome. Secondly, we performed detailed analyses of the HLA region on the same phenotypes after imputing the HLA alleles and amino acids. No protein-altering variants, or sets of protein-altering variants collapsed into genes, were associated with the main outcomes after Bonferroni correction. We found evidence that the HLA region was enriched for associations with Hand-and-Foot syndrome (p = 0.023), but no specific SNPs or HLA alleles were significant after Bonferroni correction. Larger studies will be required to characterize the genetic contribution to ADRs to 5FU. Future studies that focus on the HLA region are likely to be fruitful

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

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) in ischemic stroke and its subtypes in 3,548 cases and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 cases and 6,281 controls. We replicated reported associations between variants close to PITX2 and ZFHX3 with cardioembolic stroke, and a 9p21 locus with large vessel stroke. We identified a novel association for a SNP within the histone deacetylase 9(HDAC9) gene on chromosome 7p21.1 which was associated with large vessel stroke including additional replication in a further 735 cases and 28583 controls (rs11984041, combined P = 1.87×10−11, OR=1.42 (95% CI) 1.28-1.57). All four loci exhibit evidence for heterogeneity of effect across the stroke subtypes, with some, and possibly all, affecting risk for only one subtype. This suggests differing genetic architectures for different stroke subtypes

Genome-wide analysis in over 1 million individuals of European ancestry yields improved polygenic risk scores for blood pressure traits

Hypertension affects more than one billion people worldwide. Here we identify 113 novel loci, reporting a total of 2,103 independent genetic signals (P < 5 × 10−8) from the largest single-stage blood pressure (BP) genome-wide association study to date (n = 1,028,980 European individuals). These associations explain more than 60% of single nucleotide polymorphism-based BP heritability. Comparing top versus bottom deciles of polygenic risk scores (PRSs) reveals clinically meaningful differences in BP (16.9 mmHg systolic BP, 95% CI, 15.5–18.2 mmHg, P = 2.22 × 10−126) and more than a sevenfold higher odds of hypertension risk (odds ratio, 7.33; 95% CI, 5.54–9.70; P = 4.13 × 10−44) in an independent dataset. Adding PRS into hypertension-prediction models increased the area under the receiver operating characteristic curve (AUROC) from 0.791 (95% CI, 0.781–0.801) to 0.826 (95% CI, 0.817–0.836, ∆AUROC, 0.035, P = 1.98 × 10−34). We compare the 2,103 loci results in non-European ancestries and show significant PRS associations in a large African-American sample. Secondary analyses implicate 500 genes previously unreported for BP. Our study highlights the role of increasingly large genomic studies for precision health research

Subtype Specificity of Genetic Loci Associated With Stroke in 16 664 Cases and 32 792 Controls

Background: Genome-wide association studies have identified multiple loci associated with stroke. However, the specific stroke subtypes affected, and whether loci influence both ischemic and hemorrhagic stroke, remains unknown. For loci associated with stroke, we aimed to infer the combination of stroke subtypes likely to be affected, and in doing so assess the extent to which such loci have homogeneous effects across stroke subtypes. Methods: We performed Bayesian multinomial regression in 16 664 stroke cases and 32 792 controls of European ancestry to determine the most likely combination of stroke subtypes affected for loci with published genome-wide stroke associations, using model selection. Cases were subtyped under 2 commonly used stroke classification systems, TOAST (Trial of Org 10172 Acute Stroke Treatment) and causative classification of stroke. All individuals had genotypes imputed to the Haplotype Reference Consortium 1.1 Panel. Results: Sixteen loci were considered for analysis. Seven loci influenced both hemorrhagic and ischemic stroke, 3 of which influenced ischemic and hemorrhagic subtypes under both TOAST and causative classification of stroke. Under causative classification of stroke, 4 loci influenced both small vessel stroke and intracerebral hemorrhage. An EDNRA locus demonstrated opposing effects on ischemic and hemorrhagic stroke. No loci were predicted to influence all stroke subtypes in the same direction, and only one locus (12q24) was predicted to influence all ischemic stroke subtypes. Conclusions: Heterogeneity in the influence of stroke-associated loci on stroke subtypes is pervasive, reflecting differing causal pathways. However, overlap exists between hemorrhagic and ischemic stroke, which may reflect shared pathobiology predisposing to small vessel arteriopathy. Stroke is a complex, heterogeneous disorder requiring tailored analytic strategies to decipher genetic mechanisms

A Genotype-First Approach for the Molecular and Clinical Characterization of Uncommon De Novo Microdeletion of 20q13.33

Background: Subtelomeric deletions of the long arm of chromosome 20 are rare, with only 11 described in the literature. Clinical features of individuals with these microdeletions include severe limb malformations, skeletal abnormalities, growth retardation, developmental and speech delay, mental retardation, seizures and mild, non-specific dysmorphic features. Methodology/Principal Findings: We characterized microdeletions at 20q13.33 in six individuals referred for genetic evaluation of developmental delay, mental retardation, and/or congenital anomalies. A comparison to previously reported cases of 20q13.33 microdeletion shows phenotypic overlap, with clinical features that include mental retardation, developmental delay, speech and language deficits, seizures, and behavior problems such as autistic spectrum disorder. There does not appear to be a clinically recognizable constellation of dysmorphic features among individuals with subtelomeric 20q microdeletions. Conclusions/Significance: Based on genotype-phenotype correlation among individuals in this and previous studies, we discuss several possible candidate genes for specific clinical features, including ARFGAP1, CHRNA4 and KCNQ2 and neurodevelopmental deficits. Deletion of this region may play an important role in cognitive development

GISCOME – Genetics of Ischaemic Stroke Functional Outcome network: A protocol for an international multicentre genetic association study

© 2017, © European Stroke Organisation 2017. Introduction: Genome-wide association studies have identified several novel genetic loci associated with stroke risk, but how genetic factors influence stroke outcome is less studied. The Genetics of Ischaemic Stroke Functional outcome network aims at performing genetic studies of stroke outcome. We here describe the study protocol and methods basis of Genetics of Ischaemic Stroke Functional outcome. Methods: The Genetics of Ischaemic Stroke Functional outcome network has assembled patients from 12 ischaemic stroke projects with genome-wide genotypic and outcome data from the International Stroke Genetics Consortium and the National Institute of Neurological Diseases Stroke Genetics Network initiatives. We have assessed the availability of baseline variables, outcome metrics and time-points for collection of outcome data. Results: We have collected 8831 ischaemic stroke cases with genotypic and outcome data. Modified Rankin score was the outcome metric most readily available. We detected heterogeneity between cohorts for age and initial stroke severity (according to the NIH Stroke Scale), and will take this into account in analyses. We intend to conduct a first phase genome-wide association outcome study on ischaemic stroke cases with data on initial stroke severity and modified Rankin score within 60–190 days. To date, we have assembled 5762 such cases and are currently seeking additional cases meeting these criteria for second phase analyses. Conclusion: Genetics of Ischaemic Stroke Functional outcome is a unique collection of ischaemic stroke cases with detailed genetic and outcome data providing an opportunity for discovery of genetic loci influencing functional outcome. Genetics of Ischaemic Stroke Functional outcome will serve as an exploratory study where the results as well as the methodological observations will provide a basis for future studies on functional outcome. Genetics of Ischaemic Stroke Functional outcome can also be used for candidate gene replication or assessing stroke outcome non-genetic association hypotheses