Abstract 28: Genetic Variants From Lysine-Specific Demethylase 4C (KDM4C) Associated With White Matter Hyperintensity Burden in Ischemic Stroke Patients

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Jiang Li ◽  
Vida Abedi ◽  
Anne-Karin Giese ◽  
Markus D Schirmer ◽  
Kathleen Donahue ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
White Matter ◽  
Genetic Variants ◽  
Genome Wide Association Study ◽  
European Ancestry ◽  
White Matter Hyperintensity ◽  
Significance Level ◽  
Brain Extraction ◽  
Lysine Specific Demethylase ◽  
A Genome

Introduction: Although white matter hyperintensities (WMH) have been linked to cerebrovascular disease, the exact pathogenesis is not known. The purpose of this study was to identify common variants associated with WMH burden among patients with an acute ischemic stroke (AIS) through a genome-wide association study (GWAS). Methods: A total of 946 AIS patients with validated European ancestry and MRI data were included in this study. WMH volume (WMHv), as a quantitative trait, was calculated by a fully-automated quantification process, which integrates the automated brain extraction, intensity normalization, and WMH segmentation using spatial priors. The GWAS was carried out by a linear mixed regression model (GEMMA), adjusted for covariates, to account for the potential population structure and relatedness. The WMHv ranked in top and bottom quantile were converted to a binary trait which represent high and low WMHv subgroups. Results: The rs10815506 (MAF = 0.043; β=3.89; p=6.66E-09), at an intronic region of KDM4C , which encodes Lysine-specific demethylase 4C , was the top signal associated with WMHv. This SNP is in high linkage disequilibrium (LD) (R 2 = 0.79; D’ = 0.93) with rs35389625, a nonsynonymous variant (Asn>Ser), predicted to be pathogenic by SIFT and Polyphen. The rs35389625 was also associated with WMHv but at a lower significance level (MAF=0.040; β=3.19; p=3.21E-06). Patients with homozygous mutant alleles (GG) of rs35389625 showed significantly increased WMHv (14.93±10.15) than GA (7.94±8.48) and AA (5.09±5.85) carriers. Both rs10815506 and rs35389625 also predicted a subset of high and low WMHv group (OR=2.81, p=0.005; OR=2.42, p=0.016, respectively). No significant interaction between the top SNPs at KDM4C and other risk factors was identified in their association with WMHv. We also conducted a candidate-gene analysis by including several known SNPs, gathered from a reported meta-analysis for WMH. The frequency of MTHFR677 cytosine/thymine (rs1801133) showed difference between lower and upper quantile groups with OR=2.18 for T allele (p=0.030), the direction of which was consistent with previous studies. Conclusion: This study provides the first evidence that genetic variants at KDM4C are associated with WMH in AIS patients.

scholarly journals Recipient and donor genetic variants associated with mortality after allogeneic hematopoietic cell transplantation

2020 ◽  
Vol 4 (14) ◽  
pp. 3224-3233
Author(s):  
Paul J. Martin ◽  
David M. Levine ◽  
Barry E. Storer ◽  
Sarah C. Nelson ◽  
Xinyuan Dong ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Genetic Variants ◽  
Hematopoietic Cell Transplantation ◽  
Genome Wide Association Study ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
European Ancestry ◽  
A Genome ◽  
Grade 3 ◽  
Highly Correlated

Abstract Many studies have suggested that genetic variants in donors and recipients are associated with survival-related outcomes after allogeneic hematopoietic cell transplantation (HCT), but these results have not been confirmed. Therefore, the utility of testing genetic variants in donors and recipients for risk stratification or understanding mechanisms leading to mortality after HCT has not been established. We tested 122 recipient and donor candidate variants for association with nonrelapse mortality (NRM) and relapse mortality (RM) in a cohort of 2560 HCT recipients of European ancestry with related or unrelated donors. Associations discovered in this cohort were tested for replication in a separate cohort of 1710 HCT recipients. We found that the donor rs1051792 A allele in MICA was associated with a lower risk of NRM. Donor and recipient rs1051792 genotypes were highly correlated, making it statistically impossible to determine whether the donor or recipient genotype accounted for the association. Risks of grade 3 to 4 graft-versus-host disease (GVHD) and NRM in patients with grades 3 to 4 GVHD were lower with donor MICA-129Met but not with MICA-129Val, implicating MICA-129Met in the donor as an explanation for the decreased risk of NRM after HCT. Our analysis of candidate variants did not show any other association with NRM or RM. A genome-wide association study did not identify any other variants associated with NRM or RM.

Abstract P629: Genome-Wide Association Study of Individuals of Native Hawaiian Ancestry Reveals Unique Genetic Risk Factors for Stroke and Myocardial Infarction

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Stacy C Brown ◽  
Cameron Both ◽  
Julian N Acosta ◽  
Natalia Szejko ◽  
Victor Torres ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Ischemic Stroke ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Native Hawaiian ◽  
European Ancestry ◽  
Intronic Region ◽  
Genome Wide ◽  
A Genome ◽  
Risk Locus

Background: Several genetic susceptibility risk loci for ischemic stroke have been identified. However, the relative dearth of genetic data from populations of non-European ancestry has the potential to create disparities in access to genomics-based precision medicine strategies. Individuals of Native Hawaiian ancestry represent a particularly understudied group in stroke genomics research despite facing high rates of cerebrovascular disease. Hypothesis: Genetic variants associated with stroke differ between Native Hawaiians and previously studied groups of predominantly European ancestry. Methods: We conducted a genome-wide (GW) association study of stroke and myocardial infarction (MI) in an adult population of Native Hawaiian ancestry, using data from the Multiethnic Cohort study (MEC). Genetic information was ascertained via genome-wide array genotyping using the AB OpenArray and TaqMan platforms followed by imputation to 1000 Genomes reference panels. We pursued replication of variants that were GW significant (p<5x10 -8 ) or yielded suggestive associations (p<5x10 -7 ) in the prior stroke GW association study MEGASTROKE. Results: We identified 2,104 individuals (1,089 [51.8%] female) of Native Hawaiian ancestry, including 173 cases and 1,931 controls. We identified one novel susceptibility risk locus at a narrow intronic region located at chromosome q26.2 (top associated SNP 3:169096251, OR 2.48, 95%CI 1.81-3.41; p=1.93x10 -8 ), overlying the MECOM gene. We also identified 9 other suggestive risk loci at p<5x10 -7 . When replicating in MEGASTROKE, q26.2 did not have available counterpart variants to analyze, and 3 out of 9 suggestive signals were associated with ischemic stroke subtypes at p<0.05. Conclusions: We report the first GW association study of ischemic stroke and myocardial infarction in a Native Hawaiian population. We identified one susceptibility risk locus at q26.2, located in a narrow intronic region of MECOM, a gene that codes for a histone-lysine N-methyltransferase that has transcriptional regulation and oncoprotein functions. The lack of available replication data for this locus in the large MEGASTROKE collaboration emphasizes the importance of developing genomic resources across ancestral groups.

Abstract WP205: Pipeline for Automated White Matter Hyperintensity Segmentation in Patients With Acute Ischemic Stroke: The MRI-GENIE Study

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Markus D Schirmer ◽  
Adrian V Dalca ◽  
Ramesh Sridharan ◽  
Anne-Katrin Giese ◽  
Joseph P Broderick ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
White Matter ◽  
Acute Ischemic Stroke ◽  
Large Scale ◽  
Current Knowledge ◽  
Principal Component ◽  
White Matter Hyperintensity ◽  
Brain Extraction ◽  
Fluid Attenuated Inversion Recovery ◽  
Good Agreement

Introduction: White matter hyperintensity volume (WMHv) is an important and highly heritable cerebrovascular phenotype; however, manual or semi-automated approaches to clinically acquired MRI analysis hinder large-scale studies in acute ischemic stroke (AIS). In this work, we develop a high-throughput, fully automated WMHv analysis pipeline for clinical fluid-attenuated inversion recovery (FLAIR) images to facilitate rapid genetic discovery in AIS. Methods: Automated WMHv extraction from multiple subjects relies on significant pre-processing of medical scans, including co-registration of the images. To reduce the effects of anisotropic voxel sizes, each FLAIR image is upsampled using bi-cubic interpolation. Brain extraction is performed using RObust Brain EXtraction (ROBEX). Images are then registered to an in-house FLAIR template using Advanced Normalization Tools (ANTs). The spatial covariation of WMH is learned through principal component analysis (PCA) of manual outlines from 100 subjects. Areas of leukoaraiosis are identified and separated from other lesions using the PCA modes. Volumes are then computed using non-interpolated slices for each subject. Standard deviation (SD) in WMHv (9 subjects; 6 raters each) is calculated as a measure of variability. Good agreement between automated and manual outlines is assessed in 358 subjects (automated WMHv within 3SD of manual WMHv). Results: As part of the MRI - Gen etics I nterface E xploration (MRI-GENIE) study, WMHv were calculated on a set of 2703 FLAIR images of patients from 12 independent AIS cohorts (sites). Results are shown in Figure 1. Comparing manual and automated WMHv shows that 88% of the automated WMHv fall within 3 SD from the manual WMHv, suggesting good agreement. Conclusion: WMHv segmentation using a fully-automated pipeline for analysis of clinical MRIs is both feasible and accurate. Ongoing analysis of the extracted WMHv is expected to advance current knowledge of risks and outcomes in AIS.

scholarly journals Effects of White Matter Hyperintensities on 90-Day Functional Outcome after Large Vessel and Non-Large Vessel Stroke

2020 ◽  
Vol 49 (4) ◽  
pp. 419-426
Author(s):  
Christoph Johannes Griessenauer ◽  
David McPherson ◽  
Andrea Berger ◽  
Ping Cuiper ◽  
Nelson Sofoluke ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
White Matter ◽  
Acute Ischemic Stroke ◽  
Functional Outcome ◽  
Brain Mri ◽  
Large Vessel ◽  
Favorable Outcome ◽  
White Matter Hyperintensity ◽  
Vessel Occlusion ◽  
Brain Extraction

Introduction: White matter hyperintensity (WMH) burden is a critically important cerebrovascular phenotype related to the diagnosis and prognosis of acute ischemic stroke. The effect of WMH burden on functional outcome in large vessel occlusion (LVO) stroke has only been sparsely assessed, and direct LVO and non-LVO comparisons are currently lacking. Material and Methods: We reviewed acute ischemic stroke patients admitted between 2009 and 2017 at a large healthcare system in the USA. Patients with LVO were identified and clinical characteristics, including 90-day functional outcomes, were assessed. Clinical brain MRIs obtained at the time of the stroke underwent quantification of WMH using a fully automated algorithm. The pipeline incorporated automated brain extraction, intensity normalization, and WMH segmentation. Results: A total of 1,601 acute ischemic strokes with documented 90-day mRS were identified, including 353 (22%) with LVO. Among those strokes, WMH volume was available in 1,285 (80.3%) who had a brain MRI suitable for WMH quantification. Increasing WMH volume from 0 to 4 mL, age, female gender, a number of stroke risk factors, presence of LVO, and higher NIHSS at presentation all decreased the odds for a favorable outcome. Increasing WMH above 4 mL, however, was not associated with decreasing odds of favorable outcome. While WMH volume was associated with functional outcome in non-LVO stroke (p = 0.0009), this association between WMH and functional status was not statistically significant in the complete case multivariable model of LVO stroke (p = 0.0637). Conclusion: The burden of WMH has effects on 90-day functional outcome after LVO and non-LVO strokes. Particularly, increases from no measurable WMH to 4 mL of WMH correlate strongly with the outcome. Whether this relationship of increasing WMH to worse outcome is more pronounced in non-LVO than LVO strokes deserves additional investigation.

Abstract 136: Genetics of White Matter Hyperintensity Burden in Patients With Ischemic Stroke: The MRI-GENIE Study

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Anne-Katrin Giese ◽  
Huichun Xu ◽  
Kathleen Ryan ◽  
Markus D Schirmer ◽  
Adrian V Dalca ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
White Matter ◽  
Brain Mri ◽  
Genome Wide Association ◽  
European Ancestry ◽  
White Matter Hyperintensity ◽  
Chromosome 2 ◽  
Association Testing ◽  
Genome Wide ◽  
Mri Scans

Introduction: The MRI-Genetics Interface Exploration (MRI-GENIE) study is the first international collaboration that aims to facilitate genetic discoveries in clinical cohorts of patients with acute ischemic stroke (AIS). We have amassed the largest-to-date collection of AIS cases with brain MRI scans and genome-wide genotyping to test the role of genetic susceptibility in MRI-based cerebrovascular traits. Objective/Hypothesis: To elucidate the genetic architecture of white matter hyperintensity (WMH) burden in AIS patients. Methods: Using a novel automated algorithm, we extracted WMH volume (WMHv) from clinical MRI scans of 2704 AIS patients (age 63.1 ± 14.7 years, 60.6% male) of European ancestry. Quality control (QC) measures were undertaken per subject and per SNP, excluding subjects with non-European ancestry and poor genotyping, as well as SNPs deviating from Hardy-Weinberg equilibrium and high levels of missingness. Imputation to the Haplotype Reference Consortium (HRC version r1.1) was conducted for 1712 remaining subjects with 2.8 million SNPs on the Michigan Imputation Server. After exclusion of poorly imputed SNPs (R 2 <0.5) and SNPs with minor allele frequency < 1%, 7.7 million SNPs remained for further analysis. Genome-wide association testing of natural log-transformed WMHv on the allelic dosage per SNP was adjusted for age, sex and principal components 1-10. Results: Genome-wide association testing has identified a novel locus on chromosome 2 (T allele at rs72856504) near the LDL Receptor related Protein 1B gene (LRP1B) that was significantly associated with WMHv burden in AIS (β=0.54, SE=0.098, p=3.65*10 -8 ). Conclusion: We have identified a novel locus (T allele rs72856504) on chromosome 2 near the LRP1B gene, which is specific for WMH in AIS and has not been previosuly described in stroke-free WMH cohorts. A replication effort involving additional independent cohorts of AIS patients with brain MRI and genome-wide genotyping is ongoing.

scholarly journals White Matter Hyperintensity Quantification in Large-Scale Clinical Acute Ischemic Stroke Cohorts – The MRI-GENIE Study

2019 ◽  
Author(s):  
Markus D. Schirmer ◽  
Adrian V. Dalca ◽  
Ramesh Sridharan ◽  
Anne-Katrin Giese ◽  
Kathleen L. Donahue ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
White Matter ◽  
Acute Ischemic Stroke ◽  
Large Scale ◽  
Brain Volume ◽  
Expert Knowledge ◽  
White Matter Hyperintensity ◽  
Total Brain Volume ◽  
Brain Extraction ◽  
Total Brain

AbstractWhite matter hyperintensity (WMH) burden is a critically important cerebrovascular phenotype linked to prediction of diagnosis and prognosis of diseases, such as acute ischemic stroke (AIS). However, current approaches to its quantification on clinical MRI often rely on time intensive manual delineation of the disease on T2 fluid attenuated inverse recovery (FLAIR), which hinders high-throughput analyses such as genetic discovery.In this work, we present a fully automated pipeline for quantification of WMH in clinical large-scale studies of AIS. The pipeline incorporates automated brain extraction, intensity normalization and WMH segmentation using spatial priors. We first propose a brain extraction algorithm based on a fully convolutional deep learning architecture, specifically designed for clinical FLAIR images. We demonstrate that our method for brain extraction outperforms two commonly used and publicly available methods on clinical quality images in a set of 144 subject scans across 12 acquisition centers, based on dice coefficient (median 0.95; inter-quartile range 0.94-0.95) and Pearson correlation of total brain volume (r=0.90). Subsequently, we apply it to the large-scale clinical multi-site MRI-GENIE study (N=2783) and identify a decrease in total brain volume of -2.4cc/year. Additionally, we show that the resulting total brain volumes can successfully be used for quality control of image preprocessing.Finally, we obtain WMH volumes by building on an existing automatic WMH segmentation algorithm that delineates and distinguishes between different cerebrovascular pathologies. The learning method mimics expert knowledge of the spatial distribution of the WMH burden using a convolutional auto-encoder. This enables successful computation of WMH volumes of 2,533 clinical AIS patients. We utilize these results to demonstrate the increase of WMH burden with age (0.950 cc/year) and show that single site estimates can be biased by the number of subjects recruited.

scholarly journals Assessment of rosacea symptom severity by genome-wide association study and expression analysis highlights immuno-inflammatory and skin pigmentation genes

2018 ◽  
Vol 27 (15) ◽  
pp. 2762-2772 ◽  
Author(s):  
Jennifer L Aponte ◽  
Mathias N Chiano ◽  
Laura M Yerges-Armstrong ◽  
David A Hinds ◽  
Chao Tian ◽  
...  
Keyword(s):  
Association Study ◽  
Symptom Severity ◽  
Genome Wide Association Study ◽  
Skin Pigmentation ◽  
Genome Wide Association ◽  
European Ancestry ◽  
P Value ◽  
Significance Level ◽  
Genome Wide ◽  
A Genome

Abstract Rosacea is a common, chronic skin disease of variable severity with limited treatment options. The cause of rosacea is unknown, but it is believed to be due to a combination of hereditary and environmental factors. Little is known about the genetics of the disease. We performed a genome-wide association study (GWAS) of rosacea symptom severity with data from 73 265 research participants of European ancestry from the 23andMe customer base. Seven loci had variants associated with rosacea at the genome-wide significance level (P < 5 × 10−8). Further analyses highlighted likely gene regions or effector genes including IRF4 (P = 1.5 × 10−17), a human leukocyte antigen (HLA) region flanked by PSMB9 and HLA-DMB (P = 2.2 × 10−15), HERC2-OCA2 (P = 4.2 × 10−12), SLC45A2 (P = 1.7 × 10−10), IL13 (P = 2.8 × 10−9), a region flanked by NRXN3 and DIO2 (P = 4.1 × 10−9), and a region flanked by OVOL1and SNX32 (P = 1.2 × 10−8). All associations with rosacea were novel except for the HLA locus. Two of these loci (HERC-OCA2 and SLC45A2) and another precedented variant (rs1805007 in melanocortin 1 receptor) with an association P value just below the significance threshold (P = 1.3 × 10−7) have been previously associated with skin phenotypes and pigmentation, two of these loci are linked to immuno-inflammation phenotypes (IL13 and PSMB9-HLA-DMA) and one has been associated with both categories (IRF4). Genes within three loci (PSMB9-HLA-DMA, HERC-OCA2 and NRX3-DIO2) were differentially expressed in a previously published clinical rosacea transcriptomics study that compared lesional to non-lesional samples. The identified loci provide specificity of inflammatory mechanisms in rosacea, and identify potential pathways for therapeutic intervention.

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