scholarly journals Genome Wide Pleiotropic Analysis to Identify Novel Variants and Improve Genetic Risk Score Construction

2021 ◽  
Author(s):  
Xiaofeng Zhu ◽  
Luke Zhu ◽  
Heming Wang ◽  
Richard Cooper ◽  
Aravinda Chakravarti
Keyword(s):  
Risk Score ◽  
Genetic Risk ◽  
Mendelian Randomization ◽  
Genetic Risk Score ◽  
Modifiable Risk Factors ◽  
Summary Statistics ◽  
Genome Wide ◽  
Novel Variants ◽  
Highly Correlated ◽  
Insight Into

Abstract Systolic and diastolic blood pressure (S/DBP) are highly correlated and modifiable risk factors for cardiovascular disease (CVD). We report here a bidirectional Mendelian Randomization (MR) and GWAS pleiotropy analysis of S/DBP summary statistics from large published BP GWAS and construct a composite genetic risk score (GRS), capturing respectively 21%, 11%, and 227% more of SBP, DBP and PP heritability than achieved with the traditional GRS. The composite GRS improves the prediction of hypertension and CVD in persons of European as well as African and Asian descent. We identified and confirmed 120 novel BP pleiotropic variants that are not in linkage disequilibrium with known variants, including 17 novel BP loci. We further observed significant age-modulated genetic effects on BP, hypertension and CVD in both Europeans and Asians. Our study provides further insight into BP regulation and provides a novel way to construct a GRS for correlated traits.

scholarly journals Genome Wide Pleiotropic Analysis to Identify Novel Variants and Improve Genetic Risk Score Construction

2021 ◽  
Author(s):  
Xiaofeng Zhu ◽  
Luke Zhu ◽  
Heming Wang ◽  
Richard Cooper ◽  
Aravinda Chakravarti
Keyword(s):  
Risk Score ◽  
Genetic Risk ◽  
Mendelian Randomization ◽  
Genetic Risk Score ◽  
Modifiable Risk Factors ◽  
Summary Statistics ◽  
Genome Wide ◽  
Novel Variants ◽  
Highly Correlated ◽  
Insight Into

Abstract Systolic and diastolic blood pressure (S/DBP) are highly correlated and modifiable risk factors for cardiovascular disease (CVD). We report here a bidirectional Mendelian Randomization (MR) and GWAS pleiotropy analysis of S/DBP summary statistics from large published BP GWAS and construct a composite genetic risk score (GRS), capturing respectively 21%, 11%, and 227% more of SBP, DBP and PP heritability than achieved with the traditional GRS. The composite GRS improves the prediction of hypertension and CVD in persons of European as well as African and Asian descent. We identified and confirmed 120 novel BP pleiotropic variants that are not in linkage disequilibrium with known variants, including 17 novel BP loci. We further observed significant age-modulated genetic effects on BP, hypertension and CVD in both Europeans and Asians. Our study provides further insight into BP regulation and provides a novel way to construct a GRS for correlated traits.

scholarly journals Blood Eosinophil Count and Metabolic, Cardiac and Pulmonary Outcomes: A Mendelian Randomization Study

2018 ◽  
Vol 21 (2) ◽  
pp. 89-100 ◽  
Author(s):  
Marzyeh Amini ◽  
Judith M. Vonk ◽  
Ali Abbasi ◽  
Bram P. Prins ◽  
Marcel Bruinenberg ◽  
...  
Keyword(s):  
Risk Score ◽  
Genetic Risk ◽  
Eosinophil Count ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Genetic Risk Score ◽  
Blood Eosinophil ◽  
Summary Statistics ◽  
Blood Eosinophil Count ◽  
Genetically Determined

Blood eosinophil count is associated with a variety of common complex outcomes in epidemiological observation. The aim of this study was to explore the causal association between determined blood eosinophil count and 20 common complex outcomes (10 metabolic, 6 cardiac, and 4 pulmonary). Through Mendelian randomization, we investigated genetic evidence for the genetically determined eosinophil in association with each outcomes using individual-level LifeLines cohort data (n = 13,301), where a weighted eosinophil genetic risk score comprising five eosinophil associated variants was created. We further examined the associations of the genetically determined eosinophil with those outcomes using summary statistics obtained from genome-wide association study consortia (6 consortia and 14 outcomes). Blood eosinophil count, by a 1-SD genetically increased, was not statistically associated with common complex outcomes in the LifeLines. Using the summary statistics, we showed that a higher genetically determined eosinophil count had a significant association with lower odds of obesity (odds ratio (OR) 0.81, 95% confidence interval (CI) [0.74, 0.89]) but not with the other traits and diseases. To conclude, an elevated eosinophil count is unlikely to be causally associated to higher risk of metabolic, cardiac, and pulmonary outcomes. Further studies with a stronger genetic risk score for eosinophil count may support these results.

scholarly journals Birth weight is not causally associated with adult asthma: results from instrumental variable analyses

2018 ◽  
Author(s):  
Ping Zeng ◽  
Xinghao Yu ◽  
Xiang Zhou
Keyword(s):  
Birth Weight ◽  
Risk Score ◽  
Genetic Risk ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Genetic Risk Score ◽  
Adult Asthma ◽  
Lower Birth Weight ◽  
Genome Wide ◽  
Genetic Instruments

AbstractThe association between lower birth weight and childhood asthma is well established by observational studies. However, it remains unclear whether the influence of lower birth weight on asthma can persist into adulthood. Here, we conducted a Mendelian randomization analysis to assess the causal relationship of birth weight on the risk of adult asthma. Specifically, we carefully selected genetic instruments based on summary statistics obtained from large-scale genome-wide association meta-analyses of birth weight (up to ~160,000 individuals) and adult asthma (up to ~62,000 individuals). We performed Mendelian randomization using two separate approaches: a genetic risk score approach and a two-sample inverse-variance weighted (IVW) approach. With 37 genetic instruments for birth weight, we estimated the causal effect per one standard deviation (SD) change of birth weight to be an odds ratio (OR) of 1.00 (95% CI 0.98~1.03, p=0.737) using the genetic risk score method. We did not observe nonlinear relationship or gender difference for the estimated causal effect. In addition, with the IVW method, we estimated the causal effect of birth weight on adult asthma was observed (OR=1.02, 95% CI 0.84~1.24, p=0.813). Additionally, the iMAP method provides no additional genome-wide evidence supporting the causal effects of birth weight on adult asthma. The result of the IVW method was robust against various sensitivity analyses, and MR-PRESSO and the Egger regression showed that no instrument outliers and no horizontal pleiotropy were likely to bias the results. Overall, this Mendelian randomization study provides no evidence for the fetal origins of diseases hypothesis for adult asthma, implying that the impact of birth weight on asthma in years of children and adolescents does not persist into adult and previous findings may be biased by confounders.

Mendelian Randomization Focused Analysis of Vitamin D on the Secondary Prevention of Ischemic Stroke

Stroke ◽  
2021 ◽  
Author(s):  
Yap-Hang Chan ◽  
C. Mary Schooling ◽  
Jie Zhao ◽  
Shiu-Lun Au Yeung ◽  
Jo Jo Hai ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Vitamin D ◽  
Ischemic Stroke ◽  
Risk Score ◽  
Genetic Risk ◽  
Odds Ratio ◽  
Mendelian Randomization ◽  
De Novo ◽  
Genetic Risk Score ◽  
Ischemic Disease

Background and Purpose: Experimental studies showed vitamin D (Vit-D) could promote vascular regeneration and repair. Prior randomized studies had focused mainly on primary prevention. Whether Vit-D protects against ischemic stroke and myocardial infarction recurrence among subjects with prior ischemic insults was unknown. Here, we dissected through Mendelian randomization any effect of Vit-D on the secondary prevention of recurrent ischemic stroke and myocardial infarction. Methods: Based on a genetic risk score for Vit-D constructed from a derivation cohort sample (n=5331, 45% Vit-D deficient, 89% genotyped) via high-throughput exome-chip screening of 12 prior genome-wide association study–identified genetic variants of Vit-D mechanistic pathways ( rs2060793 , rs4588 , and rs7041 ; F statistic, 73; P <0.001), we performed a focused analysis on prospective recurrence of myocardial infarction (MI) and ischemic stroke in an independent subsample with established ischemic disease (n=441, all with prior first ischemic event; follow-up duration, 41.6±14.3 years) under a 2-sample, individual-data, prospective Mendelian randomization approach. Results: In the ischemic disease subsample, 11.1% (n=49/441) had developed recurrent ischemic stroke or MI and 13.3% (n=58/441) had developed recurrent or de novo ischemic stroke/MI. Kaplan-Meier analyses showed that genetic risk score predicted improved event-free survival from recurrent ischemic stroke or MI (log-rank, 13.0; P =0.001). Cox regression revealed that genetic risk score independently predicted reduced risk of recurrent ischemic stroke or MI combined (hazards ratio, 0.62 [95% CI, 0.48–0.81]; P <0.001), after adjusted for potential confounders. Mendelian randomization supported that Vit-D is causally protective against the primary end points of recurrent ischemic stroke or MI (Wald estimate: odds ratio, 0.55 [95% CI, 0.35–0.81]) and any recurrent or de novo ischemic stroke/MI (odds ratio, 0.64 [95% CI, 0.42–0.91]) and recurrent MI alone (odds ratio, 0.52 [95% CI, 0.30–0.81]). Conclusions: Genetically predicted lowering in Vit-D level is causal for the recurrence of ischemic vascular events in persons with prior ischemic stroke or MI.

scholarly journals Genome-wide association analysis and replication in 810,625 individuals identifies novel therapeutic targets for varicose veins

2020 ◽  
Author(s):  
Waheed-Ul-Rahman Ahmed ◽  
Akira Wiberg ◽  
Michael Ng ◽  
Wei Wang ◽  
Adam Auton ◽  
...  
Keyword(s):  
Risk Score ◽  
Genetic Risk ◽  
Varicose Veins ◽  
Genetic Risk Score ◽  
Therapeutic Targets ◽  
Genome Wide Association ◽  
Western Society ◽  
Susceptibility Loci ◽  
Genome Wide ◽  
Novel Therapeutic

AbstractBackgroundVaricose veins (VVs) affect one-third of Western society, with a significant subset of patients developing venous ulceration, and ongoing management of venous leg ulcers costing around $14.9 billion annually in the USA. There is no current medical management for VVs, with approaches limited to compression stockings, ablation techniques, or open surgery for more advanced disease. A significant proportion of patients report a positive family history, and heritability is ~17%, suggesting a strong genetic component. We aimed to identify novel therapeutic targets by improving our understanding of the aetiopathology and genetic architecture of VVs.MethodsWe performed the largest two-stage genome-wide association study of VVs in 401,656 subjects from UK Biobank, and replication in 408,969 subjects from 23andMe (total 135,514 varicose veins cases and 675,111 controls). We constructed a genetic risk score for VVs to investigate its use as a prognostic tool. Genes and pathways were prioritised using a suite of bioinformatic tools, and therapeutic targets identified using the Open Targets Platform.ResultsWe discovered 49 signals at 46 susceptibility loci associated with VVs, including 29 previously unreported genetic associations (28 susceptibility loci). We demonstrated that patients with VVs requiring surgery have a higher genetic risk score than those managed non-surgically. We map 237 genes to these loci, many of which are biologically relevant and tractable to therapeutic targeting or repurposing (notably VEGFA, COL27A1, EFEMP1, PPP3R1 and NFATC2). Tissue enrichment analyses implicated vascular tissue, and several genes were enriched in biological pathways relating to extracellular matrix biology, inflammation, angiogenesis, lymphangiogenesis, vascular smooth muscle cell migration, and apoptosis.ConclusionsGenes and pathways identified represent biologically plausible contributors to the pathobiology of VVs, identifying promising candidates for further investigation of venous biology and potential therapeutic targets. We have provided the proof-of-principle that genetic risk score correlates with disease severity, which represents a first step in personalised medicine approaches to varicose veins.

Abstract P254: Genetic Risk Score for Height and the Incidence of Venous Thromboembolism: A Prospective Study

Circulation ◽  
2016 ◽  
Vol 133 (suppl_1) ◽  
Author(s):  
Nicholas S Roetker ◽  
James S Pankow ◽  
Pamela L Lutsey ◽  
Weihong Tang ◽  
Michael A Rosenberg ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Causal Relationship ◽  
Risk Score ◽  
Genetic Risk ◽  
Mendelian Randomization ◽  
Genetic Risk Score ◽  
Statistical Significance ◽  
Body Height ◽  
Health Study ◽  
Cardiovascular Health Study

Introduction: Several observational studies have shown that taller body height is associated with greater risk of venous thromboembolism (VTE), but it is not known whether the association is causal. We used instrumental variable analysis (Mendelian randomization) to explore the causal relationship between height and VTE using a genetic risk score (GRS) for height as the instrument. Hypothesis: There is a causal relationship between taller standing height and greater risk of VTE, as demonstrated by a Mendelian randomization approach. Methods: We created a weighted GRS for height in white men and women in the Longitudinal Investigation of Thromboembolism Etiology [consisting of two longitudinal cohort studies: Atherosclerosis Risk in Communities (ARIC) and Cardiovascular Health Study (CHS)] using 668 single nucleotide polymorphisms from a recently published meta-analysis. Incident hospitalized VTE events were identified and verified by physician review of medical records. We estimated the association and causal risk differences (RD) and 95% confidence intervals (CI) for VTE incidence per standard deviation (SD) increment in height (9.4 cm). The association models were adjusted for age, sex, waist circumference, and study site. Results: There were 9,137 ARIC and 3,163 CHS participants at risk for VTE at baseline and with genetic data, and they experienced 367 (ARIC) and 105 (CHS) incident VTE events over a median 22.7 and 11.8 years of follow-up, respectively. Baseline age ranges were 45-64 and 65-98 years and mean heights were 169 and 165 cm in ARIC and CHS, respectively. The GRS was a strong instrument for height (R 2 =0.08 in ARIC and R 2 =0.07 in CHS) and had little to no correlation with other measured VTE risk factors (all R 2 ≤0.01). In ARIC, taller height was associated with greater risk of VTE [association VTE RD: 1.0% per SD in height (95% CI: 0.3 to 1.6%)]. The causal RD had the same magnitude as the association RD, but did not quite reach statistical significance [causal VTE RD per SD in height: 1.1% (95% CI: -0.3 to 2.5%)]. Predicted risks of VTE at the 10th and 90th percentiles of height (157 and 181 cm) were 2.6% and 5.4%, respectively, representing more than a doubling of risk. There was no association between height and VTE risk in CHS [association VTE RD per SD in height: 0.1% (95% CI: -1.0 to 1.2%); causal VTE RD per SD in height: -0.3% (95% CI: -2.5 to 1.9%)]. Conclusion: Taller height was associated with greater VTE risk with some supporting causal evidence in middle-aged adults from ARIC, but there was no relation between height and VTE in older adults from CHS. Future studies should further explore the causal relation between height and VTE among different age groups.

Abstract 175: Performance of a Multilocus Genetic Risk Score Derived from Top Signals in the Cardiogram+C4d Consortium in Predicting Incident Coronary Disease in the Atherosclerosis Risk in Communities Study

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Themistocles L Assimes ◽  
Benjamin Goldstein ◽  
Keyword(s):  
Risk Prediction ◽  
Risk Score ◽  
Genetic Risk ◽  
Association Studies ◽  
Genetic Risk Score ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Genotype Information ◽  
Atherosclerosis Risk

Genome wide association studies (GWAS) to date have identified 30 CAD susceptibility loci but the ability to use this information to improve risk prediction remains limited. A meta-analysis of the GWAS and Cardio Metabochip data produced by the CARDIoGRAM+C4D consortium representing 63,253 cases and 126,820 controls has identified 1885 SNPs passing a False Discovery Rate (FDR) threshold of 0.5%. We hypothesized that an expanded multi locus genetic risk score (GRS) incorporating genotype information at all loci below an FDR of 0.5% would perform better than a GRS restricted to 42 loci reaching genome wide significance and tested this hypothesis in subjects of European ancestry participating in the Atherosclerosis Risk in the Community (ARIC) study. Models testing the GRS were either minimally (age and sex) or fully adjusted for traditional risk factors (TRFs). The Figure shows the hazard ratio (HZ) and 95% CI for incident events comparing each quintile of GRS to the middle quintile. The GRS including genotype information at all loci with an FDR of 0.5% noticeably improves risk prediction over the GRS restricted to genome wide significant loci in both the minimally and fully adjusted models based on several metrics including i) HR per GRS quintile, ii) the HR per SD of the GRS, and iii) the logistic regression pseudo R2, and iv) the c statistic. The HR per GRS quintile and per SD of GRS were all lower in the fully adjusted models compared to the respective minimally adjusted models but the reduction of the HR was more striking for the models that tested the more expansive GRS. These findings suggest that a larger proportion of novel GWAS CAD loci are mediating their effects through TRFs. While these findings demonstrate some progress in risk prediction using GWAS loci, both the limited and the expanded GRS continues to explain a relatively small proportion of the overall variance compared to TRF. Thus, the clinical utility of a CAD GRS remains to be determined.

Sign in / Sign up

Export Citation Format

Share Document