Population-specific and trans-ancestry genome-wide analyses identify distinct and shared genetic risk loci for coronary artery disease

The most recent Genome-wide Association Study (GWAS) meta-analysis has reported a total of 58 genomic loci to be statistically significantly associated with genetic susceptibility to Coronary Artery Disease (CAD) (Consortium, 2015). Many of these loci also associate with other phenotypes, with the majority being lipid traits (Tada et al., 2014). But also hypertension, stroke (Dichgans et al., 2014) and migraine (Pickrell et al., 2016) appear to share genetic determinants with CAD. To functionally annotate the genomic loci harboring these association SNPs we sequenced the transcriptomes of 20 same donor human coronary artery endothelial (EC) and smooth muscle cell (SMC) lines. Deep RNA-Sequencing was used to assess Differential Gene Expression, Differential Splicing and Allele-Specific Expression. Focusing on GWAS loci for vascular phenotypes (CAD, stroke, migraine) we identified genes which display allele-specific differences in mRNA expression or splicing. We propose these genes as suitable targets for follow up studies. Consortium, C.A.D. (2015). A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease. Nature genetics 47, 1121-1130. Tada, H., Won, H.H., Melander, O., Yang, J., Peloso, G.M., and Kathiresan, S. (2014). Multiple associated variants increase the heritability explained for plasma lipids and coronary artery disease. Circulation Cardiovascular genetics 7, 583-587. Dichgans, M., Malik, R., Konig, I.R., Rosand, J., Clarke, R., Gretarsdottir, S., Thorleifsson, G., Mitchell, B.D., Assimes, T.L., Levi, C., et al. (2014). Shared genetic susceptibility to ischemic stroke and coronary artery disease: a genome-wide analysis of common variants. Stroke; a journal of cerebral circulation 45, 24-36. Pickrell, J.K., Berisa, T., Liu, J.Z., Segurel, L., Tung, J.Y., and Hinds, D.A. (2016). Detection and interpretation of shared genetic influences on 42 human traits. Nature genetics 48, 709-717.

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Polygenic risk for coronary artery disease in the Scottish and English population

BMC Cardiovascular Disorders ◽

10.1186/s12872-021-02398-4 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Chuhua Yang ◽

Fabian Starnecker ◽

Shichao Pang ◽

Zhifen Chen ◽

Ulrich Güldener ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Risk Score ◽

Genetic Risk ◽

Genetic Risk Score ◽

Individual Risk ◽

Risk Alleles ◽

Genome Wide ◽

Artery Disease ◽

Cad Risk

Abstract Background Epidemiological studies have repeatedly observed a markedly higher risk for coronary artery disease (CAD) in Scotland as compared to England. Up to now, it is unclear whether environmental or genetic factors might explain this phenomenon. Methods Using UK Biobank (UKB) data, we assessed CAD risk, based on the Framingham risk score (FRS) and common genetic variants, to explore the respective contribution to CAD prevalence in Scotland (n = 31,963) and England (n = 317,889). We calculated FRS based on sex, age, body mass index (BMI), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), systolic blood pressure (SBP), antihypertensive medication, smoking status, and diabetes. We determined the allele frequency of published genome-wide significant risk CAD alleles and a weighted genetic risk score (wGRS) for quantifying genetic CAD risk. Results Prevalence of CAD was 16% higher in Scotland as compared to England (8.98% vs. 7.68%, P < 0.001). However, the FRS only predicted a marginally higher CAD risk (less than 1%) in Scotland (12.5 ± 10.5 vs.12.6 ± 10.6, P = 0.03). Likewise, the overall number of genome-wide significant variants affecting CAD risk (157.6 ± 7.7 and 157.5 ± 7.7; P = 0.12) and a wGRS for CAD (2.49 ± 0.25 in both populations, P = 0.14) were remarkably similar in the English and Scottish population. Interestingly, we observed substantial differences in the allele frequencies of individual risk variants. Of the previously described 163 genome-wide significant variants studied here, 35 variants had higher frequencies in Scotland, whereas 37 had higher frequencies in England (P < 0.001 each). Conclusions Neither the traditional risk factors included in the FRS nor a genetic risk score (GRS) based on established common risk alleles explained the higher CAD prevalence in Scotland. However, we observed marked differences in the distribution of individual risk alleles, which emphasizes that even geographically and ethnically closely related populations may display relevant differences in the genetic architecture of a common disease.

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Sexual Differences in Genetic Predisposition of Coronary Artery Disease

Circulation Genomic and Precision Medicine ◽

10.1161/circgen.120.003147 ◽

2020 ◽

Author(s):

Yunfeng Huang ◽

Qin Hui ◽

Marta Gwinn ◽

Yi-Juan Hu ◽

Arshed A. Quyyumi ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Risk Score ◽

Genetic Risk ◽

Genetic Risk Score ◽

Risk Scores ◽

Men And Women ◽

High Genetic Risk ◽

Genome Wide ◽

Artery Disease

Background - The genomic structure that contributes to the risk of coronary artery disease (CAD) can be evaluated as a risk score of multiple variants. However, sex differences have not been fully examined in applications of genetic risk score of CAD. Methods - Using data from the UK Biobank, we constructed a CAD genetic risk score based on all known loci, three mediating trait-based (blood pressure, lipids, body mass index) sub-scores, and a genome-wide polygenic risk score based on 1.1 million variants. The differences in genetic associations with prevalent and incident CAD between men and women were investigated among 317,509 unrelated individuals of European ancestry. We also assessed interactions with sex for 161 individual loci included in the comprehensive genetic risk score. Results - For both prevalent and incident CAD, the associations of comprehensive and genome-wide genetic risk scores were stronger among men than women. Using a score of 161 loci, we observed a 2.4 times higher risk for incident CAD comparing men with high genetic risk to men with low genetic risk, but an 80 percent greater risk comparing women with high genetic risk to women with low genetic risk. (interaction p=0.002). Of the three sub-scores, the blood pressure-associated sub-score exhibited sex differences (interaction p=0.0004 per SD increase in sub-score). Analysis of individual variants identified a novel gene-sex interaction at locus 21q22.11 . Conclusions - Sexual differences in genetic predisposition should be considered in future studies of coronary artery disease, and genetic risk scores should not be assumed to perform equally well in men and women.

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Genetic Evidence for PLASMINOGEN as a Shared Genetic Risk Factor of Coronary Artery Disease and Periodontitis

Circulation Cardiovascular Genetics ◽

10.1161/circgenetics.114.000554 ◽

2015 ◽

Vol 8 (1) ◽

pp. 159-167 ◽

Cited By ~ 46

Author(s):

Arne S. Schaefer ◽

Gregor Bochenek ◽

Arne Jochens ◽

David Ellinghaus ◽

Henrik Dommisch ◽

...

Keyword(s):

Coronary Artery Disease ◽

Risk Factor ◽

Coronary Artery ◽

Genetic Risk ◽

Genetic Evidence ◽

Genetic Risk Factor ◽

Artery Disease ◽

Shared Genetic

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170 Psoriasis and coronary artery disease share a genetic risk factor through IFIH1

Journal of Investigative Dermatology ◽

10.1016/j.jid.2021.02.190 ◽

2021 ◽

Vol 141 (5) ◽

pp. S30

Author(s):

M.T. Patrick ◽

S. Sreeskandarajan ◽

Q. Li ◽

N. Mehta ◽

J.E. Gudjonsson ◽

...

Keyword(s):

Coronary Artery Disease ◽

Risk Factor ◽

Coronary Artery ◽

Genetic Risk ◽

Genetic Risk Factor ◽

Artery Disease

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Associations of observational and genetically determined caffeine intake with coronary artery disease and diabetes

European Heart Journal ◽

10.1093/ehjci/ehaa946.1493 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

A Said ◽

Y.J Van De Vegte ◽

N Verweij ◽

P Van Der Harst

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Mendelian Randomization ◽

Cox Regression ◽

Caffeine Intake ◽

Uk Biobank ◽

Genome Wide ◽

Artery Disease ◽

Genetically Determined

Abstract Background Caffeine is the most widely consumed psychostimulant and is associated with lower risk of coronary artery disease (CAD) and type 2 diabetes (T2D). However, whether these associations are causal remains unknown. Objectives This study aimed to identify genetic variants associated with caffeine intake, and to investigate possible causal links between genetically determined caffeine intake and CAD or T2D. Additionally, we aimed to replicate previous observational findings between caffeine intake and CAD or T2D. Methods Genome wide associated studies (GWAS) were performed on caffeine intake from coffee, tea or both in 407,072 UK Biobank participants. Identified variants were used in a two-sample Mendelian randomization (MR) approach to investigate evidence for causal links between caffeine intake and CAD in CARDIoGRAMplusC4D (60,801 cases; 123,504 controls) or T2D in DIAGRAM (26,676 cases; 132,532 controls). Observational associations were tested within UK Biobank using Cox regression analyses. Results Moderate observational caffeine intakes from coffee or tea were associated with lower risks of CAD or T2D compared to no or high intake, with the lowest risks at intakes of 120–180 mg/day from coffee for CAD (HR=0.77 [95% CI: 0.73–0.82; P<1e-16]), and 300–360 mg/day for T2D (HR=0.76 [95% CI: 0.67–0.86]; P=1.57e-5). GWAS identified 51 novel genetic loci associated with caffeine intake, enriched for central nervous system genes. In contrast to observational analyses, MR analyses in CARDIoGRAMplusC4D and DIAGRAM yielded no evidence for causal links between caffeine intake and the development of CAD or T2D. Conclusions MR analyses indicate caffeine intake might not protect against CAD or T2D, despite protective associations in observational analyses. Manhattan_plot_CaffeineIntake Funding Acknowledgement Type of funding source: None

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