scholarly journals Genetic variation in PLEKHG1 is associated with white matter hyperintensities (n = 11,226)

Neurology ◽  
2019 ◽  
Vol 92 (8) ◽  
pp. e749-e757 ◽  
Author(s):  
Matthew Traylor ◽  
Daniel J. Tozer ◽  
Iain D. Croall ◽  
Danuta M. Lisiecka Ford ◽  
Abiodun Olubunmi Olorunda ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Ischemic Stroke ◽  
White Matter ◽  
White Matter Hyperintensities ◽  
Small Vessel ◽  
Uk Biobank ◽  
Narrow Sense Heritability ◽  
Genome Wide ◽  
A Genome ◽  
Genome Wide Significance

ObjectiveTo identify novel genetic associations with white matter hyperintensities (WMH).MethodsWe performed a genome-wide association meta-analysis of WMH volumes in 11,226 individuals, including 8,429 population-based individuals from UK Biobank and 2,797 stroke patients. Replication of novel loci was performed in an independent dataset of 1,202 individuals. In all studies, WMH were quantified using validated automated or semi-automated methods. Imputation was to either the Haplotype Reference Consortium or 1,000 Genomes Phase 3 panels.ResultsWe identified a locus at genome-wide significance in an intron of PLEKHG1 (rs275350, β [SE] = 0.071 [0.013]; p = 1.6 × 10−8), a Rho guanine nucleotide exchange factor that is involved in reorientation of cells in the vascular endothelium. This association was validated in an independent sample (overall p value, 2.4 × 10−9). The same single nucleotide polymorphism was associated with all ischemic stroke (odds ratio [OR] [95% confidence interval (CI)] 1.07 [1.03–1.12], p = 0.00051), most strongly with the small vessel subtype (OR [95% CI] 1.09 [1.00–1.19], p = 0.044). Previous associations at 17q25 and 2p16 reached genome-wide significance in this analysis (rs3744020; β [SE] = 0.106 [0.016]; p = 1.2 × 10−11 and rs7596872; β [SE] = 0.143 [0.021]; p = 3.4 × 10−12). All identified associations with WMH to date explained 1.16% of the trait variance in UK Biobank, equivalent to 6.4% of the narrow-sense heritability.ConclusionsGenetic variation in PLEKHG1 is associated with WMH and ischemic stroke, most strongly with the small vessel subtype, suggesting it acts by promoting small vessel arteriopathy.

scholarly journals Common genetic variation indicates separate etiologies for periventricular and deep white matter hyperintensities

2019 ◽  
Author(s):  
Nicola J Armstrong ◽  
Karen A Mather ◽  
Muralidharan Sargurupremraj ◽  
Maria J Knol ◽  
Rainer Malik ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
White Matter ◽  
White Matter Hyperintensities ◽  
Meta Analysis ◽  
Neuronal Function ◽  
Deep White Matter ◽  
Genome Wide ◽  
A Genome ◽  
Genetic Overlap ◽  
Disease Subtypes

AbstractWe conducted a genome-wide association meta-analysis of two ischemic white matter disease subtypes in the brain, periventricular and deep white matter hyperintensities (PVWMH and DWMH). In 26,654 participants, we found 10 independent genome-wide significant loci only associated with PVWMH, four of which have not been described previously for total WMH burden (16q24.2, 17q21.31, 10q23.1, 7q36.1). Additionally, in both PVWMH and DWMH we observed the previous association of the 17q25.1 locus with total WMH. We found that both phenotypes have shared but also distinct genetic architectures, consistent with both different underlying and related pathophysiology. PVWMH had more extensive genetic overlap with small vessel ischemic stroke, and unique associations with several loci implicated in ischemic stroke. DWMH were characterized by associations with loci previously implicated in vascular as well as astrocytic and neuronal function. Our study confirms the utility of these phenotypes and identifies new candidate genes associated only with PVWMH.

scholarly journals Genome-wide scan in Hispanics highlights candidate loci for brain white matter hyperintensities

2017 ◽  
Vol 3 (5) ◽  
pp. e185 ◽  
Author(s):  
Ashley Beecham ◽  
Chuanhui Dong ◽  
Clinton B. Wright ◽  
Nicole Dueker ◽  
Adam M. Brickman ◽  
...  
Keyword(s):  
White Matter ◽  
Genetic Variants ◽  
White Matter Hyperintensities ◽  
Brain Mri ◽  
Intracranial Volume ◽  
Snp Analysis ◽  
Community Based ◽  
Brain White Matter ◽  
Genome Wide ◽  
A Genome

Objective:To investigate genetic variants influencing white matter hyperintensities (WMHs) in the understudied Hispanic population.Methods:Using 6.8 million single nucleotide polymorphisms (SNPs), we conducted a genome-wide association study (GWAS) to identify SNPs associated with WMH volume (WMHV) in 922 Hispanics who underwent brain MRI as a cross-section of 2 community-based cohorts in the Northern Manhattan Study and the Washington Heights–Inwood Columbia Aging Project. Multiple linear modeling with PLINK was performed to examine the additive genetic effects on ln(WMHV) after controlling for age, sex, total intracranial volume, and principal components of ancestry. Gene-based tests of association were performed using VEGAS. Replication was performed in independent samples of Europeans, African Americans, and Asians.Results:From the SNP analysis, a total of 17 independent SNPs in 7 genes had suggestive evidence of association with WMHV in Hispanics (p < 1 × 10−5) and 5 genes from the gene-based analysis with p < 1 × 10−3. One SNP (rs9957475 in GATA6) and 1 gene (UBE2C) demonstrated evidence of association (p < 0.05) in the African American sample. Four SNPs with p < 1 × 10−5 were shown to affect binding of SPI1 using RegulomeDB.Conclusions:This GWAS of 2 community-based Hispanic cohorts revealed several novel WMH-associated genetic variants. Further replication is needed in independent Hispanic samples to validate these suggestive associations, and fine mapping is needed to pinpoint causal variants.

scholarly journals Common Genetic Variation Indicates Separate Causes for Periventricular and Deep White Matter Hyperintensities

Stroke ◽  
2020 ◽  
Vol 51 (7) ◽  
pp. 2111-2121 ◽  
Author(s):  
Nicola J. Armstrong ◽  
Karen A. Mather ◽  
Muralidharan Sargurupremraj ◽  
Maria J. Knol ◽  
Rainer Malik ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
White Matter ◽  
White Matter Hyperintensities ◽  
Meta Analysis ◽  
Genetic Correlations ◽  
Imaging Genetics ◽  
Genome Wide Association ◽  
Association Analyses ◽  
New Genes ◽  
Genome Wide

Background and Purpose: Periventricular white matter hyperintensities (WMH; PVWMH) and deep WMH (DWMH) are regional classifications of WMH and reflect proposed differences in cause. In the first study, to date, we undertook genome-wide association analyses of DWMH and PVWMH to show that these phenotypes have different genetic underpinnings. Methods: Participants were aged 45 years and older, free of stroke and dementia. We conducted genome-wide association analyses of PVWMH and DWMH in 26,654 participants from CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology), ENIGMA (Enhancing Neuro-Imaging Genetics Through Meta-Analysis), and the UKB (UK Biobank). Regional correlations were investigated using the genome-wide association analyses -pairwise method. Cross-trait genetic correlations between PVWMH, DWMH, stroke, and dementia were estimated using LDSC. Results: In the discovery and replication analysis, for PVWMH only, we found associations on chromosomes 2 ( NBEAL ), 10q23.1 ( TSPAN14/FAM231A ), and 10q24.33 ( SH3PXD2A). In the much larger combined meta-analysis of all cohorts, we identified ten significant regions for PVWMH: chromosomes 2 (3 regions), 6, 7, 10 (2 regions), 13, 16, and 17q23.1. New loci of interest include 7q36.1 ( NOS3 ) and 16q24.2. In both the discovery/replication and combined analysis, we found genome-wide significant associations for the 17q25.1 locus for both DWMH and PVWMH. Using gene-based association analysis, 19 genes across all regions were identified for PVWMH only, including the new genes: CALCRL (2q32.1), KLHL24 (3q27.1), VCAN (5q27.1), and POLR2F (22q13.1). Thirteen genes in the 17q25.1 locus were significant for both phenotypes. More extensive genetic correlations were observed for PVWMH with small vessel ischemic stroke. There were no associations with dementia for either phenotype. Conclusions: Our study confirms these phenotypes have distinct and also shared genetic architectures. Genetic analyses indicated PVWMH was more associated with ischemic stroke whilst DWMH loci were implicated in vascular, astrocyte, and neuronal function. Our study confirms these phenotypes are distinct neuroimaging classifications and identifies new candidate genes associated with PVWMH only.

scholarly journals A genome-wide association study identifies that the GDF5 and COL27A1 genes are associated with knee pain in UK Biobank (N = 171, 516)

2019 ◽  
Author(s):  
Weihua Meng ◽  
Mark J Adams ◽  
Colin NA Palmer ◽  
Jingchunzi Shi ◽  
Adam Auton ◽  
...  
Keyword(s):  
Knee Pain ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Uk Biobank ◽  
Narrow Sense ◽  
Narrow Sense Heritability ◽  
Genome Wide ◽  
A Genome ◽  
The Uk

SUMMARYObjectiveKnee pain is one of the most common musculoskeletal complaints that brings people to medical attention. We sought to identify the genetic variants associated with knee pain in 171,516 subjects from the UK Biobank cohort and replicate them using cohorts from 23andMe, the Osteoarthritis Initiative (OAI), and the Johnston County Osteoarthritis Study (JoCo).MethodsWe performed a genome-wide association study of knee pain in the UK Biobank, where knee pain was ascertained through self-report and defined as “knee pain in the last month interfering with usual activities”. A total of 22,204 cases and 149,312 controls were included in the discovery analysis. We tested our top and independent SNPs (P < 5 × 10−8) for replication in 23andMe, OAI, and JoCo, then performed a joint meta-analysis between discovery and replication cohorts using GWAMA. We calculated the narrow-sense heritability of knee pain using Genome-wide Complex Trait Analysis (GCTA).ResultsWe identified 2 loci that reached genome-wide significance, rs143384 located in the GDF5 (P = 1.32 × 10−12), a gene previously implicated in osteoarthritis, and rs2808772, located near COL27A1 (P = 1.49 × 10−8). These findings were subsequently replicated in independent cohorts and increased in significance in the joint meta-analysis (rs143384: P = 4.64 × 10−18; rs2808772: P −11 = 2.56 × 10−1’). The narrow sense heritability of knee pain was 0.08.ConclusionIn this first reported genome-wide association meta-analysis of knee pain, we identified and replicated two loci in or near GDF5 and COL27A1 that are associated with knee pain.

scholarly journals A genome-wide association study links small-vessel ischemic stroke to autophagy

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Tsong-Hai Lee ◽  
Tai-Ming Ko ◽  
Chien-Hsiun Chen ◽  
Yeu-Jhy Chang ◽  
Liang-Suei Lu ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Small Vessel ◽  
Genome Wide ◽  
A Genome

scholarly journals Sustained Opening of the Blood-Brain Barrier with Progressive Accumulation of White Matter Hyperintensities Following Ischemic Stroke

2019 ◽  
Vol 9 (1) ◽  
pp. 16 ◽  
Author(s):  
Imama Naqvi ◽  
Emi Hitomi ◽  
Richard Leigh
Keyword(s):  
Ischemic Stroke ◽  
White Matter ◽  
Acute Stroke ◽  
Blood Brain Barrier ◽  
White Matter Hyperintensities ◽  
Brain Barrier ◽  
Common Finding ◽  
Blood Brain ◽  
History Of ◽  
Iv Tpa

Objective: To report a patient in whom an acute ischemic stroke precipitated chronic blood-brain barrier (BBB) disruption and expansion of vascular white matter hyperintensities (WMH) into regions of normal appearing white matter (NAWM) during the following year. Background: WMH are a common finding in patients with vascular risk factors such as a history of stroke. The pathophysiology of WMH is not fully understood; however, there is growing evidence to suggest that the development of WMH may be preceded by the BBB disruption in the NAWM. Methods: We studied a patient enrolled in the National Institutes of Health Natural History of Stroke Study who was scanned with magnetic resonance imaging (MRI) after presenting to the emergency room with an acute stroke. After a treatment with IV tPA, she underwent further MRI scanning at 2 h, 24 h, 5 days, 30 days, 90 days, 6 months, and 1-year post stroke. BBB permeability images were generated from the perfusion weighted imaging (PWI) source images. MRIs from each time point were co-registered to track changes in BBB disruption and WMH over time. Results: An 84-year-old woman presented after acute onset right hemiparesis, right-sided numbness and aphasia with an initial NIHSS of 13. MRI showed diffusion restriction in the left frontal lobe and decreased blood flow on perfusion imaging. Fluid attenuated inversion recovery (FLAIR) imaging showed bilateral confluent WMH involving the deep white matter and periventricular regions. She was treated with IV tPA without complication and her NIHSS improved initially to 3 and ultimately to 0. Permeability maps identified multiple regions of chronic BBB disruption remote from the acute stroke, predominantly spanning the junction of WMH and NAWM. The severity of BBB disruption was greatest at 24 h after the stroke but persisted on subsequent MRI scans. Progression of WMH into NAWM over the year of observation was detected bilaterally but was most dramatic in the regions adjacent to the initial stroke. Conclusions: WMH-associated BBB disruption may be exacerbated by an acute stroke, even in the contralateral hemisphere, and can persist for months after the initial event. Transformation of NAWM to WMH may be evident in areas of BBB disruption within a year after the stroke. Further studies are needed to investigate the relationship between chronic BBB disruption and progressive WMH in patients with a history of cerebrovascular disease and the potential for acute stroke to trigger or exacerbate the process leading to the development of WMH.

scholarly journals Genomic variation in the American pika: signatures of geographic isolation and implications for conservation

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Kelly B. Klingler ◽  
Joshua P. Jahner ◽  
Thomas L. Parchman ◽  
Chris Ray ◽  
Mary M. Peacock
Keyword(s):  
Genetic Variation ◽  
Genetic Structure ◽  
Sierra Nevada ◽  
Spatial Genetic Structure ◽  
Spatial Scales ◽  
Thermal Sensitivity ◽  
Genomic Variation ◽  
Genome Wide ◽  
A Genome ◽  
American Pika

Abstract Background Distributional responses by alpine taxa to repeated, glacial-interglacial cycles throughout the last two million years have significantly influenced the spatial genetic structure of populations. These effects have been exacerbated for the American pika (Ochotona princeps), a small alpine lagomorph constrained by thermal sensitivity and a limited dispersal capacity. As a species of conservation concern, long-term lack of gene flow has important consequences for landscape genetic structure and levels of diversity within populations. Here, we use reduced representation sequencing (ddRADseq) to provide a genome-wide perspective on patterns of genetic variation across pika populations representing distinct subspecies. To investigate how landscape and environmental features shape genetic variation, we collected genetic samples from distinct geographic regions as well as across finer spatial scales in two geographically proximate mountain ranges of eastern Nevada. Results Our genome-wide analyses corroborate range-wide, mitochondrial subspecific designations and reveal pronounced fine-scale population structure between the Ruby Mountains and East Humboldt Range of eastern Nevada. Populations in Nevada were characterized by low genetic diversity (π = 0.0006–0.0009; θW = 0.0005–0.0007) relative to populations in California (π = 0.0014–0.0019; θW = 0.0011–0.0017) and the Rocky Mountains (π = 0.0025–0.0027; θW = 0.0021–0.0024), indicating substantial genetic drift in these isolated populations. Tajima’s D was positive for all sites (D = 0.240–0.811), consistent with recent contraction in population sizes range-wide. Conclusions Substantial influences of geography, elevation and climate variables on genetic differentiation were also detected and may interact with the regional effects of anthropogenic climate change to force the loss of unique genetic lineages through continued population extirpations in the Great Basin and Sierra Nevada.

Quantitative Trait Loci for the Monoamine-Related Traits Heart Rate and Headless Behavior inDrosophila melanogaster

Genetics ◽  
2001 ◽  
Vol 157 (1) ◽  
pp. 283-294 ◽  
Author(s):  
Kristie Ashton ◽  
Ana Patricia Wagoner ◽  
Roland Carrillo ◽  
Greg Gibson
Keyword(s):  
Heart Rate ◽  
Genetic Variation ◽  
Recombinant Inbred Lines ◽  
Model Organism ◽  
Interval Mapping ◽  
Activity Levels ◽  
Environmental Variance ◽  
Genome Wide ◽  
A Genome ◽  
Monoamine Receptors

AbstractDrosophila melanogaster appears to be well suited as a model organism for quantitative pharmacogenetic analysis. A genome-wide deficiency screen for haploinsufficient effects on prepupal heart rate identified nine regions of the genome that significantly reduce (five deficiencies) or increase (four deficiencies) heart rate across a range of genetic backgrounds. Candidate genes include several neurotransmitter receptor loci, particularly monoamine receptors, consistent with results of prior pharmacological manipulations of heart rate, as well as genes associated with paralytic phenotypes. Significant genetic variation is also shown to exist for a suite of four autonomic behaviors that are exhibited spontaneously upon decapitation, namely, grooming, grasping, righting, and quivering. Overall activity levels are increased by application of particular concentrations of the drugs octopamine and nicotine, but due to high environmental variance both within and among replicate vials, the significance of genetic variation among wild-type lines for response to the drugs is difficult to establish. An interval mapping design was also used to map two or three QTL for each behavioral trait in a set of recombinant inbred lines derived from the laboratory stocks Oregon-R and 2b.

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