Abstract P42: Genetic Variants Associated With Vasospasm Following Aneurysmal Subarachnoid Hemorrhage

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Shantel M Weinsheimer ◽  
Matthew D Alexander ◽  
Jeffrey Nelson ◽  
Daniel L Cooke ◽  
Steven W Hetts ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Signaling Pathway ◽  
Genetic Variants ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Delayed Cerebral Ischemia ◽  
Tgf Beta ◽  
Genome Wide ◽  
Common Genetic Variants ◽  
A Genome ◽  
Snp Mapping

Background: Cerebral vasospasm is a major contributor to poor clinical outcomes in intracranial aneurysm (IA) patients and is involved in delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH). Little is known about the genetic factors associated with vasospasm pathogenesis. We performed a genome-wide association study (GWAS) to investigate association of common genetic variants with risk of vasospasm in IA patients with SAH. Methods: Our Caucasian cohort of 190 aSAH patients (121 with vasospasm diagnosed by angiography) were genotyped using UK Biobank Axiom Arrays. Genotypes were called using the Best Practices Workflow in the Axiom Analysis Suite v4.0.3.3. All samples had >97% call rate, one sample was removed due to sex mismatch, and a total of 634,781 single nucleotide polymorphisms (SNPs) with >0.01 minor allele frequency were analyzed for association with vasospasm in the final cohort of 189 cases (66.7% female, mean age 54.8 years). Logistic regression analysis was performed using an additive model adjusting for age at onset of symptoms and sex. Genome-wide significance was based on Bonferroni correction for multiple testing (P< 7.9x10 -8 ). Results: No SNPs were significantly associated with vasospasm at the genome-wide level. However, eleven SNPs were nominally associated with vasospasm (P<10E-5) including the most significant SNP mapping to an intron of GLIS3 (P=9.74E-06, OR=3.94, 95% CI: 2.15-7.22), three intronic SNPs mapping to ACVR1 , and additional SNPs mapping to introns in FSTL3 , TMEM242 , DCLK1 , one SNP upstream of RAC2 and two SNPs downstream of TEX29 and TGFBR3 , and one missense SNP mapping to MYO18B. Interestingly, two of these genes ( ACVR1 and TGFBR3 ) are in the transforming growth factor-beta (TGF-beta) signaling pathway, previously implicated in SAH pathogenesis. Conclusions: We performed a GWAS of vasospasm following aSAH. Our study suggests that common SNPs may contribute to vasospasm susceptibility following aSAH and suggests a potential role for TGF-beta signaling pathway genes in vasospasm. These findings warrant further replication in additional independent studies including other DCI outcomes.

scholarly journals Genetic Variants Correlate With Better Processing Speed

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 163-164
Author(s):  
Anastasia Gurinovich ◽  
Kaare Christensen ◽  
Marianne Nygaard ◽  
Jonas Mengel-From ◽  
Stacy Andersen ◽  
...  
Keyword(s):  
Processing Speed ◽  
Genetic Variants ◽  
Cognitive Aging ◽  
Genome Wide Association Study ◽  
Brain Aging ◽  
P Value ◽  
Digit Symbol Substitution Test ◽  
Genome Wide ◽  
Common Genetic Variants ◽  
A Genome

Abstract Some cognitive abilities, such as vocabulary, are resilient to brain aging, while others such as conceptual reasoning, memory, and processing speed, decline with age and their rate of decline is genetically regulated. Despite the strong genetic heritability of processing speed assessed by the digit symbol substitution test (DSST), previous studies have failed to identify robust common genetic variants associated with this test. The Long Life Family Study (LLFS) includes long lived individuals and their family members who maintain good DSST scores as they age and who may carry variants associated with better DSST. We therefore conducted a genome-wide association study (GWAS) of DSST in LLFS using ~15M genetic variants imputed to the HRC panel of 64,940 haplotypes with 39,635,008 sites and replicated the findings using genetic data imputed to the 1000 Genomes phase 3 reference panel combining two Danish cohorts: the Middle Aged Danish Twins and the Longitudinal Study of Aging Danish Twins. The GWAS in LLFS discovered 20 rare genetic variants reaching genome-wide significance (p-value &lt; 5x10-8), including 18 variants associated with better processing speed with large effect size. The genetic associations of rs7623455, rs9821776, rs9821587, rs78704059 in chromosome 3 were replicated in the combined Danish cohort. These genetic variants tagged two hormone receptor related genes, THRB and RARB, both related to cognitive aging. Further gene-based tests in LLFS confirmed that these two genes have protective variants associated with better processing speed.

A genome-wide association identified the common genetic variants influence disease severity in β0-thalassemia/hemoglobin E

2009 ◽  
Vol 127 (3) ◽  
pp. 303-314 ◽  
Author(s):  
Manit Nuinoon ◽  
Wattanan Makarasara ◽  
Taisei Mushiroda ◽  
Iswari Setianingsih ◽  
Pustika Amalia Wahidiyat ◽  
...  
Keyword(s):  
Disease Severity ◽  
Genetic Variants ◽  
Genome Wide Association ◽  
Hemoglobin E ◽  
Genome Wide ◽  
Common Genetic Variants ◽  
A Genome ◽  
The Common

scholarly journals Association of common genetic variants in the CPSF7 and SDHAF2 genes with Canine Idiopathic Pulmonary Fibrosis in the West Highland White Terrier

2020 ◽  
Author(s):  
Ignazio S. Piras ◽  
Christiane Bleul ◽  
Ashley Siniard ◽  
Amanda J. Wolfe ◽  
Matthew D. De Both ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Genetic Variants ◽  
Genome Wide Association Study ◽  
Nucleotide Polymorphisms ◽  
The West ◽  
Genome Wide ◽  
Common Genetic Variants ◽  
A Genome ◽  
Fibrotic Lung Disease

AbstractCanine Idiopathic Pulmonary Fibrosis (CIPF) is a chronic fibrotic lung disease that is observed at a higher frequency in the West Highland White Terrier dog breed (WHWT) and may have molecular pathological overlap with human lung fibrotic disease. We conducted a Genome-Wide Association Study (GWAS) in the WHWT using Whole Genome Sequencing (WGS) to discover genetic variants associated with CIPF. Saliva-derived DNA samples were sequenced using the Riptide™ DNA library prep kit. After quality controls, 28 affected, 44 unaffected and 1,843,695 informative Single Nucleotide Polymorphisms (SNPs) were included in the GWAS. Data were analyzed both at the single SNP and gene levels using the GEMMA and GATES methods, respectively. We detected significant signals at the gene level in both the CPSF7 and SDHAF2 genes (adjusted p = 0.016 and p = 0.025, respectively), two overlapping genes located on chromosome 18. The top SNP for both genes was rs22669389, however it did not reach genome-wide significance in the GWAS (adjusted p = 0.078). Our studies provide, for the first time, candidate loci for CIPF in the WHWT. CPSF7 was recently associated with lung adenocarcinoma further highlighting the potential relevance of our results since IPF and lung cancer share several pathological mechanisms.

scholarly journals A Genome-wide Comparison of the Functional Properties of Rare and Common Genetic Variants in Humans

2011 ◽  
Vol 88 (4) ◽  
pp. 458-468 ◽  
Author(s):  
Qianqian Zhu ◽  
Dongliang Ge ◽  
Jessica M. Maia ◽  
Mingfu Zhu ◽  
Slave Petrovski ◽  
...  
Keyword(s):  
Functional Properties ◽  
Genetic Variants ◽  
Genome Wide ◽  
Common Genetic Variants ◽  
A Genome

scholarly journals GENOME-WIDE ASSOCIATION STUDY OF EXTREME HUMAN LONGEVITY DISCOVERS UNCOMMON LONGEVITY VARIANTS

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S209-S209
Author(s):  
Anastasia Gurinovich ◽  
Anastasia Gurinovich ◽  
Zeyuan Song ◽  
Stacy L Andersen ◽  
Thomas T Perls ◽  
...  
Keyword(s):  
Association Study ◽  
Genetic Variants ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Genome Wide Association ◽  
Human Longevity ◽  
Mixed Effect ◽  
Genome Wide ◽  
Common Genetic Variants ◽  
A Genome

Abstract The strong heritability of extreme human longevity supports the hypothesis that this is a genetically-regulated trait. However, association studies focused on common genetic variants have discovered a limited number of longevity-associated genes. We conducted a genome-wide association study of 4,216 individuals including 1317 centenarians from the New England Centenarian Study (median age = 104 years) using &gt;9M genetic variants imputed to the HRC panel of ~65,000 haplotypes. The set included approximately 5M uncommon variants. The associations were tested using a mixed effect logistic regression model with genotype-based kinship covariance of the random effects to adjust for cryptic relations using the package GENESIS. The analysis discovered 45 genome-wide significant SNPs (p&lt; 5E-08) including 8 new loci in chromosomes 3, 6, 7, 9, 10, 14 and 15 in addition to the APOE locus. The list includes new pQTLs in serum that suggest a new biological mechanism involved in extreme human longevity.

scholarly journals Estimating the heritability of reporting stressful life events captured by common genetic variants

2012 ◽  
Vol 43 (9) ◽  
pp. 1965-1971 ◽  
Author(s):  
R. A. Power ◽  
T. Wingenbach ◽  
S. Cohen-Woods ◽  
R. Uher ◽  
M. Y. Ng ◽  
...  
Keyword(s):  
Life Events ◽  
Genetic Variants ◽  
Stressful Life Events ◽  
Genome Wide Association Study ◽  
Significant Proportion ◽  
Stressful Life ◽  
Phenotypic Variance ◽  
Genome Wide ◽  
Common Genetic Variants ◽  
A Genome

BackgroundAlthough usually thought of as external environmental stressors, a significant heritable component has been reported for measures of stressful life events (SLEs) in twin studies.MethodWe examined the variance in SLEs captured by common genetic variants from a genome-wide association study (GWAS) of 2578 individuals. Genome-wide complex trait analysis (GCTA) was used to estimate the phenotypic variance tagged by single nucleotide polymorphisms (SNPs). We also performed a GWAS on the number of SLEs, and looked at correlations between siblings.ResultsA significant proportion of variance in SLEs was captured by SNPs (30%, p = 0.04). When events were divided into those considered to be dependent or independent, an equal amount of variance was explained for both. This ‘heritability’ was in part confounded by personality measures of neuroticism and psychoticism. A GWAS for the total number of SLEs revealed one SNP that reached genome-wide significance (p = 4 × 10−8), although this association was not replicated in separate samples. Using available sibling data for 744 individuals, we also found a significant positive correlation of R2 = 0.08 in SLEs (p = 0.03).ConclusionsThese results provide independent validation from molecular data for the heritability of reporting environmental measures, and show that this heritability is in part due to both common variants and the confounding effect of personality.

scholarly journals Association of Common Genetic Variants in the CPSF7 and SDHAF2 Genes with Canine Idiopathic Pulmonary Fibrosis in the West Highland White Terrier

Genes ◽  
2020 ◽  
Vol 11 (6) ◽  
pp. 609
Author(s):  
Ignazio S. Piras ◽  
Christiane Bleul ◽  
Ashley Siniard ◽  
Amanda J. Wolfe ◽  
Matthew D. De Both ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Genetic Variants ◽  
Genome Wide Association Study ◽  
Specific Factor ◽  
Nucleotide Polymorphisms ◽  
The West ◽  
Genome Wide ◽  
Common Genetic Variants ◽  
A Genome

Canine idiopathic pulmonary fibrosis (CIPF) is a chronic fibrotic lung disease that is observed at a higher frequency in the West Highland White Terrier dog breed (WHWT) and may have molecular pathological overlap with human lung fibrotic disease. We conducted a genome-wide association study (GWAS) in the WHWT using whole genome sequencing (WGS) to discover genetic variants associated with CIPF. Saliva-derived DNA samples were sequenced using the Riptide DNA library prep kit. After quality controls, 28 affected, 44 unaffected, and 1,843,695 informative single nucleotide polymorphisms (SNPs) were included in the GWAS. Data were analyzed both at the single SNP and gene levels using the GEMMA and GATES methods, respectively. We detected significant signals at the gene level in both the cleavage and polyadenylation specific factor 7 (CPSF7) and succinate dehydrogenase complex assembly factor 2 (SDHAF2) genes (adjusted p = 0.016 and 0.024, respectively), two overlapping genes located on chromosome 18. The top SNP for both genes was rs22669389; however, it did not reach genome-wide significance in the GWAS (adjusted p = 0.078). Our studies provide, for the first time, candidate loci for CIPF in the WHWT. CPSF7 was recently associated with lung adenocarcinoma, further highlighting the potential relevance of our results because IPF and lung cancer share several pathological mechanisms.

scholarly journals crisprQTL mapping as a genome-wide association framework for cellular genetic screens

2018 ◽  
Author(s):  
Molly Gasperini ◽  
Andrew J. Hill ◽  
José L. McFaline-Figueroa ◽  
Beth Martin ◽  
Cole Trapnell ◽  
...  
Keyword(s):  
Linkage Disequilibrium ◽  
Genetic Variants ◽  
Target Gene ◽  
Genome Wide Association ◽  
Eqtl Mapping ◽  
Rna Seq ◽  
Naturally Occurring ◽  
Genome Wide ◽  
Common Genetic Variants ◽  
A Genome

AbstractExpression quantitative trait locus (eQTL) and genome-wide association studies (GWAS) are powerful paradigms for mapping the determinants of gene expression and organismal phenotypes, respectively. However, eQTL mapping and GWAS are limited in scope (to naturally occurring, common genetic variants) and resolution (by linkage disequilibrium). Here, we present crisprQTL mapping, a framework in which large numbers of CRISPR/Cas9 perturbations are introduced to each cell on an isogenic background, followed by single-cell RNA-seq (scRNA-seq). crisprQTL mapping is analogous to conventional human eQTL studies, but with individual humans replaced by individual cells; genetic variants replaced by unique combinations of ‘unlinked’ guide RNA (gRNA)-programmed perturbations per cell; and tissue-level RNA-seq of many individuals replaced by scRNA-seq of many cells. By randomly introducing gRNAs, a single population of cells can be leveraged to test for association between each perturbation and the expression of any potential target gene, analogous to how eQTL studies leverage populations of humans to test millions of genetic variants for associations with expression in a genome-wide manner. However, crisprQTL mapping is neither limited to naturally occurring, common genetic variants nor by linkage disequilibrium. As a proof-of-concept, we applied crisprQTL mapping to evaluate 1,119 candidate enhancers with no strong a priori hypothesis as to their target gene(s). Perturbations were made by a nuclease-dead Cas9 (dCas9) tethered to KRAB, and introduced at a mean ‘allele frequency’ of 1.1% into a population of 47,650 profiled human K562 cells (median of 15 gRNAs identified per cell). We tested for differential expression of all genes within 1 megabase (Mb) of each candidate enhancer, effectively evaluating 17,584 potential enhancer-target gene relationships within a single experiment. At an empirical false discovery rate (FDR) of 10%, we identify 128 cis crisprQTLs (11%) whose targeting resulted in downregulation of 105 nearby genes. crisprQTLs were strongly enriched for proximity to their target genes (median 34.3 kilobases (Kb)) and the strength of H3K27ac, p300, and lineage-specific transcription factor (TF) ChIP-seq peaks. Our results establish the power of the eQTL mapping paradigm as applied to programmed variation in populations of cells, rather than natural variation in populations of individuals. We anticipate that crisprQTL mapping will facilitate the comprehensive elucidation of the cis-regulatory architecture of the human genome.

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