Abstract 154: Genetic Variants in CETP That Increase HDL Levels also Increase Risk of Intracerebral Hemorrhage

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Guido J Falcone ◽  
Chia-Ling Phuah ◽  
Farid Radmanesh ◽  
Gina M Peloso ◽  
James F Meschia ◽  
...  
Keyword(s):  
Intracerebral Hemorrhage ◽  
Dna Sequence ◽  
Genetic Variants ◽  
Association Studies ◽  
Sequence Variants ◽  
Genome Wide Association Studies ◽  
Discovery Phase ◽  
Increased Risk ◽  
Increase Risk ◽  
Dna Sequence Variants

Introduction: In observational studies, higher plasma high-density lipoprotein cholesterol (HDL-C) has been associated with increased risk of spontaneous intracerebral hemorrhage (ICH). Common DNA sequence variants within the cholesteryl ester transfer protein ( CETP ) gene decrease CETP protein activity and increase plasma HDL-C; as such, medicines that inhibit CETP and raise HDL-C are in clinical development to combat coronary artery disease. Hypothesis: Common CETP DNA sequence variants associated with higher HDL-C also increase risk for ICH. Methods: We performed a two-stage case-control genetic association study in Caucasians. The discovery phase utilized data on 12 independent loci within CETP (+/- 50 kilobases) from 3 genome-wide association studies of ICH. Replication involved direct genotyping in 5 additional studies. We also constructed a genetic risk score with 7 independent CETP variants and tested it for association with HDL-C and ICH risk. We used principal component analysis to account for population structure and a Bonferroni-adjusted p<0.004 (12 tests) to declare statistical significance. Results: The discovery phase included 1149 ICH cases (43% lobar hemorrhages) and 1238 controls. Twelve variants were nominally associated (p<0.05) with ICH, with the strongest association at the rs173539 locus (Figure 1: OR 1.25, 95%CI 1.11-1.41; p=6.0x10 -4 ) and no heterogeneity across studies (I 2 =0%). This association was replicated in 1625 cases (43% lobar hemorrhages) and 1845 controls (OR 1.12, 95%CI 1.02-1.24; p=0.03). A genetic score of independent CETP variants known to increase HDL-C by ~2.85 mg/dL was strongly associated with ICH risk (OR 1.86, 95%CI 1.44-2.40; p=1.4x10 -6 ). Conclusion: Genetic variants in CETP associated with increased HDL-C raise the risk of ICH. Given ongoing therapeutic development in CETP inhibition and other HDL-raising strategies, further exploration of potential adverse cerebrovascular outcomes is warranted.

scholarly journals Integrative Genomic Analysis for the Discovery of Biomarkers in Prostate Cancer

2014 ◽  
Vol 9 ◽  
pp. BMI.S13729 ◽  
Author(s):  
Chindo Hicks ◽  
Tejaswi Koganti ◽  
Shankar Giri ◽  
Memory Tekere ◽  
Ritika Ramani ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Gene Expression Data ◽  
Genetic Variants ◽  
Association Studies ◽  
Biological Pathways ◽  
Great Success ◽  
Genome Wide Association Studies ◽  
Expression Data ◽  
Increased Risk

Genome-wide association studies (GWAS) have achieved great success in identifying single nucleotide polymorphisms (SNPs, herein called genetic variants) and genes associated with risk of developing prostate cancer. However, GWAS do not typically link the genetic variants to the disease state or inform the broader context in which the genetic variants operate. Here, we present a novel integrative genomics approach that combines GWAS information with gene expression data to infer the causal association between gene expression and the disease and to identify the network states and biological pathways enriched for genetic variants. We identified gene regulatory networks and biological pathways enriched for genetic variants, including the prostate cancer, IGF-1, JAK2, androgen, and prolactin signaling pathways. The integration of GWAS information with gene expression data provides insights about the broader context in which genetic variants associated with an increased risk of developing prostate cancer operate.

scholarly journals Exome sequencing and genotyping identify a rare variant in NLRP7 gene associated with ulcerative colitis

2017 ◽  
Author(s):  
Alexandros Onoufriadis ◽  
Kristina Stone ◽  
Antreas Katsiamides ◽  
Ariella Amar ◽  
Yasmin Omar ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Exome Sequencing ◽  
Genetic Variants ◽  
Odds Ratio ◽  
High Throughput Sequencing ◽  
Association Studies ◽  
Common Disease ◽  
Genome Wide Association Studies ◽  
Increased Risk ◽  
Coding Variants

AbstractBackground and aimsAlthough genome-wide association studies (GWAS) in inflammatory bowel disease (IBD) have identified a large number of common disease susceptibility alleles for both Crohn’s disease (CD) and ulcerative colitis (UC), a substantial fraction of IBD heritability remains unexplained, suggesting that rare coding genetic variants may also have a role in pathogenesis. We used high-throughput sequencing in families with multiple cases of IBD, followed by genotyping of cases and controls, to investigate whether rare protein altering genetic variants are associated with susceptibility to IBD.MethodsWhole exome sequencing was carried out in 10 families in which 3 or more individuals were affected with IBD. A stepwise filtering approach was applied to exome variants to identify potential causal variants. Follow-up genotyping was performed in 6,025 IBD cases (2,948 CD; 3,077 UC) and 7,238 controls.ResultsOur exome variant analysis revealed coding variants in the NLRP7 gene that were present in affected individuals in two distinct families. Genotyping of the two variants, p.S361L and p.R801H, in IBD cases and controls showed that the p.S361L variant was significantly associated with an increased risk of ulcerative colitis (odds ratio 4.79, p=0.0039) and IBD (odds ratio 3.17, p=0.037). A combined analysis of both variants showed suggestive association with an increased risk of IBD (odds ratio 2.77, p=0.018).ConclusionsThe results suggest that NLRP7 signalling and inflammasome formation may be a significant component in the pathogenesis of IBD.

Clinical implication of telomere length-related polymorphisms in gastric cardia adenocarcinoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15502-e15502
Author(s):  
Nasha Zhang ◽  
Ming Yang
Keyword(s):  
Telomere Length ◽  
Genetic Variants ◽  
Association Studies ◽  
Gastric Cardia ◽  
Candidate Snps ◽  
Gastric Cardia Adenocarcinoma ◽  
Genome Wide Association Studies ◽  
Critical Feature ◽  
Increased Risk ◽  
The Impact

e15502 Background: Aberrant telomere lengthening is a critical feature of malignant cells. Short leukocyte telomere length (LTL) confers elevated risk of gastric cardia adenocarcinoma (GCA). Multiple genome-wide association studies (GWAS) identified various single nucleotide polymorphisms (SNPs) associated with LTL in different ethnic populations. However, it remains largely unexplored how these genetic variants are involved in GCA susceptibility. Methods: We systematically screened GWAS-identified candidate SNPs and tested the impact of thirty polymorphisms in genes associated with interindividual LTL variation on GCA using two-stage case-control comparisons consisting of 1,024 GCA patients and 1,118 controls. Results: We observed that CXCR4 rs6430612, TERT rs10069690 and rs2853676 as well as VPS34 rs2162440 are significantly associated with GCA development. A 0.64-fold decreased risk of GCA is associated with the CXCR4 rs6430612 CT genotype compared with the CC genotype ( P= 0.002). On the contrary, the TERT rs10069690 TT genotype carriers had a 1.83-fold increased risk to develop GCA compared to the CC genotype carriers ( P= 5.8×10-6). We also detected a 2.17-fold increased OR for GCA that was associated with the TERT rs2853676 TT genotype ( P= 2.6×10-6). In addition, the odds of having the VPS34 rs2162440 GA genotype in GCA patients was 1.35 compared with the GG genotype ( P= 0.002). In stratified analyses, the association between TERT rs10069690 polymorphism and GCA was more pronounced in nonsmokers ( Pinteraction=9.7×10-5) and nondrinkers ( Pinteraction= 4.6×10-5). Conclusions: Our results highlight the importance of both LTL and LTL-related genetic variants to GCA predisposition.

scholarly journals Functional Deletion/Insertion Promoter Variants in SCARB1 Associated With Increased Susceptibility to Lipid Profile Abnormalities and Coronary Heart Disease

2022 ◽  
Vol 8 ◽  
Author(s):  
Senlin Hu ◽  
Dong Hu ◽  
Haoran Wei ◽  
Shi-yang Li ◽  
Dong Wang ◽  
...  
Keyword(s):  
Coronary Heart Disease ◽  
Heart Disease ◽  
Genetic Variants ◽  
Promoter Region ◽  
Association Studies ◽  
Density Lipoprotein ◽  
Genome Wide Association Studies ◽  
Control Subjects ◽  
Functional Variants ◽  
Increased Risk

Background: Genetic variants in Scavenger receptor Class B Type 1 (SCARB1) influencing high-density lipoprotein cholesterol (HDL-C) and coronary heart disease (CHD) risk were identified by recent genome-wide association studies. Further study of potential functional variants in SCARB1 may provide new ideas of the complicated relationship between HDL-C and CHD.Methods: 2000 bp in SCARB1 promoter region was re-sequenced in 168 participants with extremely high plasma HDL-C and 400 control subjects. Putative risk alleles were identified using bioinformatics analysis and reporter-gene assays. Two indel variants, rs144334493 and rs557348251, respectively, were genotyped in 5,002 CHD patients and 5,175 control subjects. The underlying mechanisms were investigated.Results: Through resequencing, 27 genetic variants were identified. Results of genotyping in 5,002 CHD patients and 5,175 control subjects revealed that rs144334493 and rs557348251 were significantly associated with increased risk of CHD [odds ratio (OR): 1.28, 95% confidence interval (CI): 1.09 to 1.52, p = 0.003; OR: 2.65, 95% CI: 1.66–4.24, p = 4.4 × 10−5). Subsequent mechanism experiments demonstrated that rs144334493 deletion allele attenuated forkhead box A1 (FOXA1) binding to the promoter region of SCARB1, while FOXA1 overexpression reversely increased SR-BI expression.Conclusion: Genetic variants in SCARB1 promoter region significantly associated with the plasma lipid levels by affecting SR-BI expression and contribute to the susceptibility of CHD.

scholarly journals Colorectal cancer susceptibility variants and risk of conventional adenomas and serrated polyps: results from three cohort studies

2019 ◽  
Vol 49 (1) ◽  
pp. 259-269 ◽  
Author(s):  
Dong Hang ◽  
Amit D Joshi ◽  
Xiaosheng He ◽  
Andrew T Chan ◽  
Manol Jovani ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cohort Studies ◽  
Genetic Variants ◽  
Association Studies ◽  
Genetic Risk Score ◽  
Genome Wide Association Studies ◽  
Serrated Polyps ◽  
Common Genetic Variants ◽  
Increased Risk ◽  
Weighted Genetic Risk Score

Abstract Background Increasing evidence suggests that conventional adenomas (CAs) and serrated polyps (SPs) represent two distinct groups of precursor lesions for colorectal cancer (CRC). The influence of common genetic variants on risk of CAs and SPs remain largely unknown. Methods Among 27 426 participants within three prospective cohort studies, we created a weighted genetic risk score (GRS) based on 40 CRC-related single nucleotide polymorphisms (SNPs) identified in previous genome-wide association studies; and we examined the association of GRS (per one standard deviation increment) with risk of CAs, SPs and synchronous CAs and SPs, by multivariable logistic regression. We also analysed individual variants in the secondary analysis. Results During 18–20 years of follow-up, we documented 2952 CAs, 1585 SPs and 794 synchronous CAs and SPs. Higher GRS was associated with increased risk of CAs [odds ratio (OR) = 1.17, 95% confidence interval (CI): 1.12-1.21] and SPs (OR = 1.09, 95% CI: 1.03-1.14), with a stronger association for CAs than SPs (Pheterogeneity=0.01). An even stronger association was found for patients with synchronous CAs and SPs (OR = 1.32), advanced CAs (OR = 1.22) and multiple CAs (OR = 1.25). Different sets of variants were associated with CAs and SPs, with a Spearman correlation coefficient of 0.02 between the ORs associating the 40 SNPs with the two lesions. After correcting for multiple testing, three variants were associated with CAs (rs3802842, rs6983267 and rs7136702) and two with SPs (rs16892766 and rs4779584). Conclusions Common genetic variants play a potential role in the conventional and serrated pathways of CRC. Different sets of variants are identified for the two pathways, further supporting the aetiological heterogeneity of CRC.

scholarly journals Modifiable lifestyle factors and severe COVID-19 risk: a Mendelian randomisation study

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Shuai Li ◽  
Xinyang Hua
Keyword(s):  
Physical Activity ◽  
Alcohol Consumption ◽  
Genetic Variants ◽  
Association Studies ◽  
Lifestyle Factors ◽  
Mendelian Randomisation ◽  
Severe Illness ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Increased Risk

Abstract Background Lifestyle factors including obesity and smoking are suggested to be correlated with increased risk of COVID-19 severe illness or related death. However, whether these relationships are causal is not well known; neither for the relationships between COVID-19 severe illness and other common lifestyle factors, such as physical activity and alcohol consumption. Methods Genome-wide significant genetic variants associated with body mass index (BMI), lifetime smoking, physical activity and alcohol consumption identified by large-scale genome-wide association studies (GWAS) of up to 941,280 individuals were selected as instrumental variables. Summary statistics of the genetic variants on severe illness of COVID-19 were obtained from GWAS analyses of up to 6492 cases and 1,012,809 controls. Two-sample Mendelian randomisation analyses were conducted. Results Both per-standard deviation (SD) increase in genetically predicted BMI and lifetime smoking were associated with about two-fold increased risks of severe respiratory COVID-19 and COVID-19 hospitalization (all P < 0.05). Per-SD increase in genetically predicted physical activity was associated with decreased risks of severe respiratory COVID-19 (odds ratio [OR] = 0.19; 95% confidence interval [CI], 0.05, 0.74; P = 0.02), but not with COVID-19 hospitalization (OR = 0.44; 95% CI 0.18, 1.07; P = 0.07). No evidence of association was found for genetically predicted alcohol consumption. Similar results were found across robust Mendelian randomisation methods. Conclusions Evidence is found that BMI and smoking causally increase and physical activity might causally decrease the risk of COVID-19 severe illness. This study highlights the importance of maintaining a healthy lifestyle in protecting from COVID-19 severe illness and its public health value in fighting against COVID-19 pandemic.

Genetics in anxiety disorders - an update

2011 ◽  
Vol 26 (S2) ◽  
pp. 2097-2097
Author(s):  
K. Domschke
Keyword(s):  
Panic Disorder ◽  
Anxiety Disorders ◽  
Candidate Genes ◽  
Genetic Variants ◽  
Emotional Processing ◽  
Disease Risk ◽  
Association Studies ◽  
Imaging Genetics ◽  
Genome Wide Association Studies ◽  
Increased Risk

Twin studies propose a strong genetic contribution to the pathogenesis of anxiety disorders with a heritability of about 50%. The dissection of the complex-genetic underpinnings of anxiety disorders requires a multi-level approach using molecular genetic, imaging genetic, (cognitive)-behavioral genetic and pharmacogenetic techniques linking basic and clinical research.The present talk will first give an overview of results from linkage and association studies yielding support for several candidate genes contributing to the genetic risk for anxiety and panic disorder in particular such as the adenosine 2A receptor, the catechol-O-methyltransferase, the neuropeptide S receptor and the serotonin receptor 1A genes. Results from the first genome-wide association studies in the field of anxiety disorders will be discussed. Additionally, studies on gene-environment interactions between anxiety disorder risk variants and environmental factors will be presented. Imaging genetics approaches have yielded evidence for several risk genes to crucially impact activation in brain regions critical for emotional processing. Gene variation has furthermore been found to potentially confer an increased risk for panic disorder via elevated autonomic arousal and dysfunctional cognitions regarding bodily sensations. Finally, there is first evidence for genetic variants impacting treatment response to antidepressant pharmacotherapy in anxiety disorders.Thus, converging lines of evidence will be presented for several candidate genes of anxiety to exert an increased disease risk potentially via a distorted cortico-limbic interaction during emotional processing, increased physiological arousal or dysfunctional cognition. Additionally, a possible impact of genetic variants on pharmacoresponse in anxiety disorders and its potential clinical implications will be discussed.

scholarly journals A Genome-Wide Association Study of spontaneous preterm birth in a European population

F1000Research ◽  
2013 ◽  
Vol 2 ◽  
pp. 255 ◽  
Author(s):  
Wilfred Wu ◽  
Erin A S Clark ◽  
Tracy A Manuck ◽  
M Sean Esplin ◽  
Michael W Varner ◽  
...  
Keyword(s):  
Preterm Birth ◽  
Genetic Variants ◽  
Association Studies ◽  
European Population ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Spontaneous Preterm Birth ◽  
Genome Wide ◽  
A Genome ◽  
Increased Risk

Background: Preterm birth is defined as a birth prior to 37 completed weeks’ gestation. It affects more than 10% of all births worldwide, and is the leading cause of neonatal mortality in non-anomalous newborns. Even if the preterm newborn survives, there is an increased risk of lifelong morbidity. Despite the magnitude of this public health problem, the etiology of spontaneous preterm birth is not well understood. Previous studies suggest that genetics is an important contributing factor. We therefore employed a genome-wide association approach to explore possible fetal genetic variants that may be associated with spontaneous preterm birth.Methods: We obtained preterm birth phenotype and genotype data from the National Center for Biotechnology Information Genotypes and Phenotypes Database (study accession phs000103.v1.p1). This dataset contains participants collected by the Danish National Birth Cohort and includes 1000 preterm births and 1000 term births as controls. Whole genomes were genotyped on the Illumina Human660W-Quad_v1_A platform, which contains more than 500,000 markers. After data quality control, we performed genome-wide association studies for the 22 autosomal chromosomes.Results: No single nucleotide polymorphism reached genome-wide significance after Bonferroni correction for multiple testing.Conclusion: We found no evidence of genetic association with spontaneous preterm birth in this European population. Approaches that facilitate detection of both common and rare genetic variants, such as evaluation of high-risk pedigrees and genome sequencing, may be more successful in identifying genes associated with spontaneous preterm birth.

scholarly journals A Phenome-Wide Association Study of genes associated with COVID-19 severity reveals shared genetics with complex diseases in the Million Veteran Program

2021 ◽  
Author(s):  
Anurag Verma ◽  
Noah L. Tsao ◽  
Lauren O. Thomann ◽  
Yuk-Lam Ho ◽  
Rotonya Carr ◽  
...  
Keyword(s):  
Association Study ◽  
Genetic Variants ◽  
Genetic Architecture ◽  
Association Studies ◽  
Missense Variant ◽  
International Classification Of Diseases ◽  
Genome Wide Association Studies ◽  
Increased Risk ◽  
Significant Difference ◽  
Shared Genetic

Background There are certain pre-existing conditions which leads in increased risk of coronavirus disease 2019 (COVID-19) severity and mortality. The objective of this study is to determine shared genetic architecture between COVID-19 severity and other medical conditions using electronic health record (EHR) data from diverse patient populations. Methods and Findings: We conducted Phenome-wide association study (PheWAS) of genetic variants associated with severe COVID-19 in two biobanks with EHR and genomic data: 1) Veteran Affairs (VA) Million Veteran Program (MVP), 2) United Kingdom Biobank (UKBB). Genetic variants associated with critical illness (n=48) or hospitalization (n=39) due to COVID-19 from COVID-19 Host Genetics Initiative genome-wide association studies. Phenotypes defined by International Classification of Diseases (ICD) codes mapped to clinically relevant groups using published PheWAS methods; pre-COVID-19 data used to avoid potential confounding. Among 455,683 US Veterans from MVP, variants associated with severe COVID-19 tested for association across 1,559 phenotypes; 353,365 UK Biobank participants, and 1,064 phenotypes tested. Genetic variants at ABO locus (rs550057, rs505922) associated with the largest number of phenotypes (nrs55057= 53 and nrs505922=61); strongest association with venous embolism, odds ratio (OR)rs550057 1.27 (p=5.28 x 10-116), and thrombosis ORrs505922 1.31, p=3.5 x10-183. Among 67 respiratory conditions tested, only idiopathic pulmonary fibrosis, OR rs2277732 1.17, p=1.3410-05, and asthma ORrs143334143 0.94, p=2.31 x10-04, shared variants with severe COVID-19. The RAVER1 locus (rs74956615) associated with reduced risk for autoimmune conditions, e.g. psoriasis OR 0.71, p= 1.53 x10-22, rheumatoid arthritis, OR 0.78, p=1.04 x 10-09; findings replicated in UKBB. A known functional missense variant (rs34536443, TYK2) in the region had the highest linkage disequilibrium with rs74956615, suggesting signal was likely from TYK2. In MVP, PheWAS results stratified by genetic ancestry did not demonstrate significant difference in associations across ancestry. Conclusions Shared genetic architecture between COVID-19 severity and conditions related to underlying risk factors for severe and poor COVID-19 outcomes; associations similar across genetic ancestries. Divergent association between inflammatory conditions and severe COVID may be explained by known pathway impairing signaling of inflammatory cytokines, reducing risk for autoimmunity; same pathway reduces type 1 interferon signaling, critical for viral host defense. Caution needed when targeting pathways that may balance immune tolerance and immunodeficiency to treat COVID-19.

scholarly journals Rare variants contribute disproportionately to quantitative trait variation in yeast

2019 ◽  
Author(s):  
Joshua S Bloom ◽  
James Boocock ◽  
Sebastian Treusch ◽  
Meru J Sadhu ◽  
Laura Day ◽  
...  
Keyword(s):  
Dna Sequence ◽  
Effect Size ◽  
Quantitative Trait ◽  
Rare Variants ◽  
Sequence Variants ◽  
Genome Wide Association Studies ◽  
Size Estimation ◽  
Heritable Variation ◽  
Trait Variation ◽  
Dna Sequence Variants

AbstractA detailed understanding of the sources of heritable variation is a central goal of modern genetics. Genome-wide association studies (GWAS) in humans1 have implicated tens of thousands of DNA sequence variants in disease risk and quantitative trait variation, but these variants fail to account for the entire heritability of diseases and traits. GWAS have by design focused on common DNA sequence variants; however, recent studies underscore the likely importance of the contribution of rare variants to heritable variation2. Further, finding the genes that underlie the GWAS signals remains a major challenge. Here, we use a unique model system to disentangle the contributions of common and rare variants to a large number of quantitative traits. We generated large crosses among 16 diverse yeast strains and identified thousands of quantitative trait loci (QTLs) that explain most of the heritable variation in 38 traits. We combined our results with sequencing data for 1,011 yeast isolates3 to decouple variant effect size estimation from allele frequency and showed that rare variants make a disproportionate contribution to trait variation as a consequence of their larger effect sizes. Evolutionary analyses revealed that this contribution is driven by rare variants that arose recently, that such variants are more likely to decrease fitness, and that negative selection has shaped the relationship between variant frequency and effect size. Finally, we leveraged the structure of the crosses to resolve hundreds of QTLs to single genes. These results refine our understanding of trait variation at the population level and suggest that studies of rare variants are a fertile ground for discovery of genetic effects.

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