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 Using genetics to understand the causal influence of higher BMI on depression

2018 ◽  
Vol 48 (3) ◽  
pp. 834-848 ◽  
Author(s):  
Jessica Tyrrell ◽  
Anwar Mulugeta ◽  
Andrew R Wood ◽  
Ang Zhou ◽  
Robin N Beaumont ◽  
...  
Keyword(s):  
Risk Score ◽  
Genetic Risk ◽  
Mendelian Randomization ◽  
Genetic Risk Score ◽  
Self Report ◽  
Uk Biobank ◽  
Men And Women ◽  
Statistical Confidence ◽  
The Uk ◽  
Genetically Determined

Abstract Background Depression is more common in obese than non-obese individuals, especially in women, but the causal relationship between obesity and depression is complex and uncertain. Previous studies have used genetic variants associated with BMI to provide evidence that higher body mass index (BMI) causes depression, but have not tested whether this relationship is driven by the metabolic consequences of BMI nor for differences between men and women. Methods We performed a Mendelian randomization study using 48 791 individuals with depression and 291 995 controls in the UK Biobank, to test for causal effects of higher BMI on depression (defined using self-report and Hospital Episode data). We used two genetic instruments, both representing higher BMI, but one with and one without its adverse metabolic consequences, in an attempt to ‘uncouple’ the psychological component of obesity from the metabolic consequences. We further tested causal relationships in men and women separately, and using subsets of BMI variants from known physiological pathways. Results Higher BMI was strongly associated with higher odds of depression, especially in women. Mendelian randomization provided evidence that higher BMI partly causes depression. Using a 73-variant BMI genetic risk score, a genetically determined one standard deviation (1 SD) higher BMI (4.9 kg/m2) was associated with higher odds of depression in all individuals [odds ratio (OR): 1.18, 95% confidence interval (CI): 1.09, 1.28, P = 0.00007) and women only (OR: 1.24, 95% CI: 1.11, 1.39, P = 0.0001). Meta-analysis with 45 591 depression cases and 97 647 controls from the Psychiatric Genomics Consortium (PGC) strengthened the statistical confidence of the findings in all individuals. Similar effect size estimates were obtained using different Mendelian randomization methods, although not all reached P < 0.05. Using a metabolically favourable adiposity genetic risk score, and meta-analysing data from the UK biobank and PGC, a genetically determined 1 SD higher BMI (4.9 kg/m2) was associated with higher odds of depression in all individuals (OR: 1.26, 95% CI: 1.06, 1.50], P = 0.010), but with weaker statistical confidence. Conclusions Higher BMI, with and without its adverse metabolic consequences, is likely to have a causal role in determining the likelihood of an individual developing depression.

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 Mendelian randomization provides evidence for a causal effect of higher serum IGF-1 concentration on risk of hip and knee osteoarthritis

Rheumatology ◽  
2020 ◽  
Author(s):  
April Hartley ◽  
Eleanor Sanderson ◽  
Lavinia Paternoster ◽  
Alexander Teumer ◽  
Robert C Kaplan ◽  
...  
Keyword(s):  
Risk Score ◽  
Genetic Risk ◽  
Odds Ratio ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Genetic Risk Score ◽  
Uk Biobank ◽  
Knee Oa ◽  
Increased Risk

Abstract Objectives How insulin-like growth factor-1 (IGF-1) is related to OA is not well understood. We determined relationships between IGF-1 and hospital-diagnosed hand, hip and knee OA in UK Biobank, using Mendelian randomization (MR) to determine causality. Methods Serum IGF-1 was assessed by chemiluminescent immunoassay. OA was determined using Hospital Episode Statistics. One-sample MR (1SMR) was performed using two-stage least-squares regression, with an unweighted IGF-1 genetic risk score as an instrument. Multivariable MR included BMI as an additional exposure (instrumented by BMI genetic risk score). MR analyses were adjusted for sex, genotyping chip and principal components. We then performed two-sample MR (2SMR) using summary statistics from Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) (IGF-1, N = 30 884) and the recent genome-wide association study meta-analysis (N = 455 221) of UK Biobank and Arthritis Research UK OA Genetics (arcOGEN). Results A total of 332 092 adults in UK Biobank had complete data. Their mean (s.d.) age was 56.5 (8.0) years and 54% were female. IGF-1 was observationally related to a reduced odds of hand OA [odds ratio per doubling = 0.87 (95% CI 0.82, 0.93)], and an increased odds of hip OA [1.04 (1.01, 1.07)], but was unrelated to knee OA [0.99 (0.96, 1.01)]. Using 1SMR, we found strong evidence for an increased risk of hip [odds ratio per s.d. increase = 1.57 (1.21, 2.01)] and knee [1.30 (1.07, 1.58)] OA with increasing IGF-1 concentration. By contrast, we found no evidence for a causal effect of IGF-1 concentration on hand OA [0.98 (0.57, 1.70)]. Results were consistent when estimated using 2SMR and in multivariable MR analyses accounting for BMI. Conclusion We have found evidence that increased serum IGF-1 is causally related to higher risk of hip and knee OA.

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.

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.

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.

scholarly journals A Genome-Wide Association Study of the Frailty Index Highlights Synaptic Pathways in Aging

2019 ◽  
Author(s):  
Janice L Atkins ◽  
Juulia Jylhävä ◽  
Nancy L Pedersen ◽  
Patrik K Magnusson ◽  
Yi Lu ◽  
...  
Keyword(s):  
Association Study ◽  
Risk Score ◽  
Genetic Risk ◽  
Genome Wide Association Study ◽  
Genetic Risk Score ◽  
Frailty Index ◽  
Genome Wide Association ◽  
Uk Biobank ◽  
Genome Wide ◽  
A Genome

ABSTRACTFrailty is a common geriatric syndrome, strongly associated with disability, mortality and hospitalisation. The mechanisms underlying frailty are multifactorial and not well understood, but a genetic basis has been suggested with heritability estimates between 19 and 45%. Understanding the genetic determinants and biological mechanisms underpinning frailty may help to delay or even prevent frailty. We performed a genome-wide association study (GWAS) of a frailty index (FI) in European descent participants from UK Biobank (n=164,610, aged 60-70 years). FI calculation was based on 49 self-reported items on symptoms, disabilities and diagnosed diseases. We identified 26 independent genetic signals at 24 loci associated with the FI (p<5*10−8). Many of these loci have previously been associated with traits such as body mass index, cardiovascular disease, smoking, HLA proteins, depression and neuroticism; however, three appear to be novel. The estimated single nucleotide polymorphism (SNP) heritability of the FI was 14% (0.14, SE 0.006). A genetic risk score for the FI, derived solely from the UK Biobank data, was significantly associated with FI in the Swedish TwinGene study (n=10,616, beta: 0.11, 95% CI: 0.02-0.20, p=0.015). In pathway analysis, genes associated with synapse function were significantly enriched (p<3*10−6). We also used Mendelian randomization to identify modifiable traits and exposures that may affect the risk of frailty, with a higher educational attainment genetic risk score being associated with a lower risk of frailty. Risk of frailty is influenced by many genetic factors, including well-known disease risk factors and mental health, with particular emphasis on synapse maintenance pathways.

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