scholarly journals Multi-ancestry genetic study in 5,876 patients identifies an association between excitotoxic genes and early outcomes after acute ischemic stroke

2020 ◽  
Author(s):  
Laura Ibanez ◽  
Laura Heitsch ◽  
Caty Carrera ◽  
Fabiana H.G. Farias ◽  
Rajat Dhar ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Genetic Study ◽  
Genetic Architecture ◽  
Stroke Onset ◽  
Neurological Deficits ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Synaptic Protein ◽  
Genome Wide

ABSTRACTDuring the first hours after stroke onset neurological deficits can be highly unstable: some patients rapidly improve, while others deteriorate. This early neurological instability has a major impact on long-term outcome. Here, we aimed to determine the genetic architecture of early neurological instability measured by the difference between NIH stroke scale (NIHSS) within six hours of stroke onset and NIHSS at 24h (ΔNIHSS). A total of 5,876 individuals from seven countries (Spain, Finland, Poland, United States, Costa Rica, Mexico and Korea) were studied using a multi-ancestry meta-analyses. We found that 8.7% of ΔNIHSS variance was explained by common genetic variations, and also that early neurological instability has a different genetic architecture than that of stroke risk. Seven loci (2p25.1, 2q31.2, 2q33.3, 4q34.3, 5q33.2, 6q26 and 7p21.1) were genome-wide significant and explained 2.1% of the variability suggesting that additional variants influence early change in neurological deficits. We used functional genomics and bioinformatic annotation to identify the genes driving the association from each loci. eQTL mapping and SMR indicate that ADAM23 (log Bayes Factor (LBF)=6.34) was driving the association for 2q33.3. Gene based analyses suggested that GRIA1 (LBF=5.26), which is predominantly expressed in brain, is the gene driving the association for the 5q33.2 locus. These analyses also nominated PARK2 (LBF=5.30) and ABCB5 (LBF=5.70) for the 6q26 and 7p21.1 loci. Human brain single nuclei RNA-seq indicates that the gene expression of ADAM23 and GRIA1 is enriched in neurons. ADAM23, a pre-synaptic protein, and GRIA1, a protein subunit of the AMPA receptor, are part of a synaptic protein complex that modulates neuronal excitability. These data provides the first evidence in humans that excitotoxicity may contribute to early neurological instability after acute ischemic stroke.RESEARCH INTO CONTEXTEvidence before this studyNo previous genome-wide association studies have investigated the genetic architecture of early outcomes after ischemic stroke.Added Value of this studyThis is the first study that investigated genetic influences on early outcomes after ischemic stroke using a genome-wide approach, revealing seven genome-wide significant loci. A unique aspect of this genetic study is the inclusion of all of the major ethnicities by recruiting from participants throughout the world. Most genetic studies to date have been limited to populations of European ancestry.Implications of all available evidenceThe findings provide the first evidence that genes implicating excitotoxicity contribute to human acute ischemic stroke, and demonstrates proof of principle that GWAS of acute ischemic stroke patients can reveal mechanisms involved in ischemic brain injury.

Abstract 76: Genome Wide Association Study of Early Neurological Deterioration after Acute Ischemic Stroke Defines the Interferon-Stimulated Gene IFIT1 as a Neuroprotective Factor

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Laura Heitsch ◽  
Andrew Kraft ◽  
Kristin Guilliams ◽  
Andria Ford ◽  
Naim Khoury ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Pathway Analysis ◽  
Genome Wide Association Study ◽  
Stroke Onset ◽  
Neurological Deficits ◽  
Stroke Patients ◽  
Long Term Outcome ◽  
Genome Wide ◽  
Variant Analysis

Introduction: In the first hours after ischemic stroke, neurological deficits can be highly unstable. These early neurological changes are important due to their influence on long-term outcome. We performed a GWAS on ΔNIHSS 24h (NIHSS change from baseline to 24 hours after stroke onset) in acute ischemic stroke patients. Methods: DNA from 191 stroke patients presenting within 4.5 hours of stroke onset was genotyped using an Affymetrix Exome-chip. Single variant analysis was performed using PLINK, including age, baseline NIHSS and principal component factors as covariates. European- and African-Americans were analyzed separately, with p-values combined by meta-analysis. Gene-based analysis was performed using SKAT-O, including only non-synonymous variants. Pathway analysis was performed using ALIGATOR to identify pathways with SNPs with significant associations. IFIT1 -/- and IFIT1 +/+ mice underwent one-hour MCA occlusion (tMCAO) followed by 24-hour reperfusion. Brains were removed, TTC-stained, and infarcts measured. Results: Single variant analysis did not reveal genome-wide significant associations. One gene, IFIT1 (interferon-induced protein with tetratricopeptide repeats), passed the gene-based genome-wide multiple test correction (A). All three polymorphic variants in IFIT1 associated with neurologic deterioration with an average ΔNIHSS 24h 9.5 points lower in carriers versus non-carriers (B). Pathway analysis, including 21 interferon-related genes but excluding IFIT1 , showed a highly significant association (p=2.30х10 -3 ) with ΔNIHSS 24h. Infarct volumes in IFIT1 -/- mice were twice the size of IFIT1 +/+ mice after tMCAO (C, 110.6 mm 3 vs 52.8 mm 3 ). Conclusion: These data suggest that IFIT1 and other interferon-related genes may function in endogenous neuroprotective responses during acute ischemic stroke.

Abstract WMP113: Genetic Influences on Early Neurological Instability After Acute Ischemic Stroke

Stroke ◽  
2016 ◽  
Vol 47 (suppl_1) ◽  
Author(s):  
Laura Ibanez ◽  
Laura Heitsch ◽  
Caty Carrera ◽  
Israel Fernandez ◽  
Joan Montaner ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Neurological Outcome ◽  
Cohort Analysis ◽  
Neurological Deficits ◽  
Genetic Influences ◽  
Common Variants ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Genome Wide

Following acute ischemic stroke (AIS) onset, neurological deficits can be highly unstable. Early neurological change within the first 24 hours, defined here as ΔNIHSS24h (NIHSSbaseline-NIHSS24hours), substantially influences long-term outcome. While several mechanisms, such as hemorrhagic transformation and recanalization, may impact ΔNIHSS24h, little is known about genetic influences. Genetic variants associated with ΔNIHSS24h may identify genes involved in mechanisms of early neurological outcome after AIS. AIS patients were prospectively enrolled between 2008-2014 at two sites (St Louis and BCN; Table 1). NIHSS scores were obtained within 6 hours and again at 24 hours after stroke onset. Genome-wide genotyping was generated for rare and common variants, imputing up to 6 million single nucleotide polymorphisms (SNPs) for all subjects (N=891). ΔNIHSS24h was used as a quantitative trait to measure early improvement/deterioration. Genome-wide complex trait analysis (GCTA) was performed. An association model was done, using NIHSSbaseline, age, gender, glucose, PCA1 and PCA2 as covariates. All samples were analyzed together and then separately by ethnicity (Spanish, European-American (EA), and African-American (AA)). GCTA indicates that common variants account for 23-28% of ΔNIHSS24h variability. VAV3 rs72689643 (p=8.21x10-8) was associated with ΔNIHSS24h in the whole cohort analysis (Figure 1). Three additional suggestive SNPs were found: 2 intergenic SNPs (rs139950151 and rs73706194 - both p=6.1x10-7) in high LD and SNP rs10431426 (p=1.71x10-7) located in an intron. When analyzed by ethnicity, these findings did not reach GWAs significance, likely due to lack of power. Early neurological outcome after AIS is strongly influenced by genetics. Vav3 shows association with ΔNIHSS24h in the whole cohort while several other SNPs are suggestive. Rare variant analysis is underway, and we will also have an additional 800 genotypes analyzed by ISC.

scholarly journals A meta-analysis of genome-wide association studies for average daily gain and lean meat percentage in two Duroc pig populations

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Shenping Zhou ◽  
Rongrong Ding ◽  
Fanming Meng ◽  
Xingwang Wang ◽  
Zhanwei Zhuang ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Growth And Development ◽  
Genetic Architecture ◽  
Association Studies ◽  
Meta Analysis ◽  
Average Daily Gain ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Daily Gain

Abstract Background Average daily gain (ADG) and lean meat percentage (LMP) are the main production performance indicators of pigs. Nevertheless, the genetic architecture of ADG and LMP is still elusive. Here, we conducted genome-wide association studies (GWAS) and meta-analysis for ADG and LMP in 3770 American and 2090 Canadian Duroc pigs. Results In the American Duroc pigs, one novel pleiotropic quantitative trait locus (QTL) on Sus scrofa chromosome 1 (SSC1) was identified to be associated with ADG and LMP, which spans 2.53 Mb (from 159.66 to 162.19 Mb). In the Canadian Duroc pigs, two novel QTLs on SSC1 were detected for LMP, which were situated in 3.86 Mb (from 157.99 to 161.85 Mb) and 555 kb (from 37.63 to 38.19 Mb) regions. The meta-analysis identified ten and 20 additional SNPs for ADG and LMP, respectively. Finally, four genes (PHLPP1, STC1, DYRK1B, and PIK3C2A) were detected to be associated with ADG and/or LMP. Further bioinformatics analysis showed that the candidate genes for ADG are mainly involved in bone growth and development, whereas the candidate genes for LMP mainly participated in adipose tissue and muscle tissue growth and development. Conclusions We performed GWAS and meta-analysis for ADG and LMP based on a large sample size consisting of two Duroc pig populations. One pleiotropic QTL that shared a 2.19 Mb haplotype block from 159.66 to 161.85 Mb on SSC1 was found to affect ADG and LMP in the two Duroc pig populations. Furthermore, the combination of single-population and meta-analysis of GWAS improved the efficiency of detecting additional SNPs for the analyzed traits. Our results provide new insights into the genetic architecture of ADG and LMP traits in pigs. Moreover, some significant SNPs associated with ADG and/or LMP in this study may be useful for marker-assisted selection in pig breeding.

scholarly journals The anesthetic approach for endovascular recanalization therapy depends on the lesion site in acute ischemic stroke

2021 ◽  
Author(s):  
Kilian Fröhlich ◽  
Gabriela Siedler ◽  
Svenja Stoll ◽  
Kosmas Macha ◽  
Thomas M. Kinfe ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Middle Cerebral Artery ◽  
Acute Ischemic Stroke ◽  
Cerebral Artery ◽  
Posterior Circulation ◽  
Neurological Deficits ◽  
Stroke Severity ◽  
Lesion Volume ◽  
Middle Cerebral Artery Territory ◽  
Cerebral Lesion

Abstract Purpose Endovascular therapy (EVT) of large-vessel occlusion in acute ischemic stroke (AIS) may be performed in general anesthesia (GA) or conscious sedation (CS). We intended to determine the contribution of ischemic cerebral lesion sites on the physician’s decision between GA and CS using voxel-based lesion symptom mapping (VLSM). Methods In a prospective local database, we sought patients with documented AIS and EVT. Age, stroke severity, lesion volume, vigilance, and aphasia scores were compared between EVT patients with GA and CS. The ischemic lesions were analyzed on CT or MRI scans and transformed into stereotaxic space. We determined the lesion overlap and assessed whether GA or CS is associated with specific cerebral lesion sites using the voxel-wise Liebermeister test. Results One hundred seventy-nine patients with AIS and EVT were included in the analysis. The VLSM analysis yielded associations between GA and ischemic lesions in the left hemispheric middle cerebral artery territory and posterior circulation areas. Stroke severity and lesion volume were significantly higher in the GA group. The prevalence of aphasia and aphasia severity was significantly higher and parameters of vigilance lower in the GA group. Conclusions The VLSM analysis showed associations between GA and ischemic lesions in the left hemispheric middle cerebral artery territory and posterior circulation areas including the thalamus that are known to cause neurologic deficits, such as aphasia or compromised vigilance, in AIS-patients with EVT. Our data suggest that higher disability, clinical impairment due to neurological deficits like aphasia, or reduced alertness of affected patients may influence the physician’s decision on using GA in EVT.

scholarly journals Intra-domain task-adaptive transfer learning to determine acute ischemic stroke onset time

2021 ◽  
Vol 90 ◽  
pp. 101926
Author(s):  
Haoyue Zhang ◽  
Jennifer S Polson ◽  
Kambiz Nael ◽  
Noriko Salamon ◽  
Bryan Yoo ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Transfer Learning ◽  
Onset Time ◽  
Stroke Onset

scholarly journals Genetics of complex traits: prediction of phenotype, identification of causal polymorphisms and genetic architecture

2016 ◽  
Vol 283 (1835) ◽  
pp. 20160569 ◽  
Author(s):  
M. E. Goddard ◽  
K. E. Kemper ◽  
I. M. MacLeod ◽  
A. J. Chamberlain ◽  
B. J. Hayes
Keyword(s):  
Complex Traits ◽  
Genetic Architecture ◽  
Quantitative Traits ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Crop Breeding ◽  
Single Nucleotide ◽  
Genome Wide ◽  
Phenotype Identification

Complex or quantitative traits are important in medicine, agriculture and evolution, yet, until recently, few of the polymorphisms that cause variation in these traits were known. Genome-wide association studies (GWAS), based on the ability to assay thousands of single nucleotide polymorphisms (SNPs), have revolutionized our understanding of the genetics of complex traits. We advocate the analysis of GWAS data by a statistical method that fits all SNP effects simultaneously, assuming that these effects are drawn from a prior distribution. We illustrate how this method can be used to predict future phenotypes, to map and identify the causal mutations, and to study the genetic architecture of complex traits. The genetic architecture of complex traits is even more complex than previously thought: in almost every trait studied there are thousands of polymorphisms that explain genetic variation. Methods of predicting future phenotypes, collectively known as genomic selection or genomic prediction, have been widely adopted in livestock and crop breeding, leading to increased rates of genetic improvement.

Abstract TP476: White Matter Hyperintensity Burden is Associated With Poor Collateral Flow and Worse Outcomes in an Acute Ischemic Stroke Cohort

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Rami-James Assadi ◽  
Hongyu An ◽  
Yasheng Chen ◽  
Andria Ford ◽  
Jin-Moo Lee
Keyword(s):  
Ischemic Stroke ◽  
White Matter ◽  
Acute Ischemic Stroke ◽  
Pearson Correlation ◽  
Stroke Onset ◽  
White Matter Hyperintensity ◽  
Flow Index ◽  
Acute Ischemia ◽  
Collateral Flow ◽  
Core Volume

Introduction: White matter hyperintensity volume (WMHv), a quantitative neuroimaging biomarker of cerebral small vessel disease (CSVD), is associated worse outcomes after ischemic stroke. In this study, we hypothesized that worse outcomes in CSVD patients were due to poor collateral flow during acute ischemia. Methods: 47 patients with acute ischemic stroke (AIS) were prospectively enrolled in this study. Serial MRIs were performed at 3 hours and 30 days after stroke onset. 3-hour FLAIR images were used to determine WMHv, after manually delineating lesions with MIPAV. An index of collateral flow (delayed perfusion to the penumbra) was determined by subtracting core volume (volume of tissue with ADC<600) from the volume of brain tissue with Tmax>2. Patient’s NIHSS was scored at 3 hours and 30 days after stroke onset and the difference was calculated (ΔNIHSS). Log-transformed WMHv was correlated to ΔNIHSS and the collateral flow index, using Pearson correlation. Results: Mean age = 63.9 years (SD 13.5); 37% female; median 3-hour NIHSS = 13 (IQR 6.5-20); median change in NIHSS between 3h and 30d = 4 (IQR: 0-7); median core volume = 13cm3 (IQR 4.3-35.6); median WMHv = 1.257cm3 (IQR 641-3595). WMHv was associated with reduced improvement in ΔNIHSS (R=-0.42, ρ=0.005). Furthermore, WMHv demonstrated a trend for association with poor collateral flow (R=-0.28, ρ=0.062). In this dataset, we will explore the relationship between WMHv and other tissue-based metrics of collateral flow, including the hypoperfusion intensity ratio (HIR) and the cerebral blood volume ratio (rCBV). Conclusions: Our study confirms that patients with CSVD have worse outcomes after AIS. The data also raise the possibility that these worse outcomes in CSVD patients may be mediated by compromised collateral flow in the setting of acute ischemia.

Abstract P359: A Sickle Cell Variant Associates With Urine Albumin Excretion in Genome Wide Association Study of Hispanics: The HCHS/SOL Study

Circulation ◽  
2015 ◽  
Vol 131 (suppl_1) ◽  
Author(s):  
Nora Franceschini ◽  
Adrienne Stilp ◽  
Christina L Wassel ◽  
Holly J Mattix-Kramer ◽  
Michael F Flessner ◽  
...  
Keyword(s):  
Allele Frequency ◽  
Sickle Cell ◽  
Missense Variant ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Minority Population ◽  
Genome Wide Association Studies ◽  
Urine Albumin ◽  
Genome Wide ◽  
A Genome

Introduction: Genome wide association studies have identified genetic variants in the Cubillin gene ( CUBN ) that explain inter-individual variation in urine albumin-to-creatinine excretion (UACR) in populations. These studies have not included Hispanics/Latinos, the fast growing minority population in the U.S., who has also high prevalence of chronic kidney disease and its risk factors. Hypothesis: By leveraging on population admixture of Hispanics and using a genome wide association approach, we hypothesized that novel loci associated with UACR would be identified. Methods: We used data from 12,212 self-identified Hispanic individuals recruited in a community-based study, aged 18-74 years at screening (2008-2011), and randomly selected from households in four U.S. field centers (Chicago, IL; Miami, FL; Bronx, NY; San Diego, CA). Urine albumin (mg/dl) and creatinine (g/dl) were measured at the baseline exam. UACR was log-transformed for analysis. Individuals were excluded if reporting to have end-stage renal disease. Genotyping was performed using a custom Illumina Omni2.5M array. Imputation of variants was performed using 1000 Genome Project data from cosmopolitan HapMap samples. After quality control of imputed data, we performed mixed linear regression analyses that accounted for the sampling strategy and family relatedness, for variants with minor allele frequency (MAF) > 0.01 and imputation quality > 0.3. We used additive genetic models and adjusted for age, sex, and principal components which were estimated from the data. In a secondary analysis, we also examine the association of significant variants with kidney function using estimated glomerular filtration rate (eGFR) equations. Results: Among 12,212 participants, 41% were men, and mean age was 46 (SD =13). There was little evidence for genome wide inflation (lambda =1.024). We identified significant associations of single nucleotide polymorphisms (SNPs) with UACR at two loci: CUBN and HBB . The CUBN SNP (chr10:16966414, p=2.1x10-8) is an indel variant with MAF of 0.14, which was not in linkage disequilibrium with previously reported SNP rs1801239 (rsq=0.38, p=1.3x10-4) identified in individuals of European ancestry. The HBB SNP is a missense variant which results in an E [Glu] ⇒ A [Ala] substitution in the beta-globin chain of hemoglobin and a cause of the Mendelian disorder sickle cell anemia (rs334, T allele frequency =0.01, beta=0.44, SE=0.06, p=7.6x10-12). rs344 was not associated with eGFR in our data (p>0.05). Conclusion: This study identified a novel association of a sickle cell missense variant with UACR in Hispanics, and provided evidence for allelic heterogeneity at the CUBN locus. Our findings suggest a role for Mendelian gene variants in increased albuminuria in Hispanic populations with admixture.

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.

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