Genetics of Common, Complex Coronary Artery Disease

Musunuru, Kiran; Kathiresan, Sekar

doi:10.1016/j.cell.2019.02.015

Cited by 200 publications

(145 citation statements)

References 118 publications

(128 reference statements)

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“…Variants in or near CELSR2 have been previously associated with cholesterol, response to statins, lipoprotein-associated phospholipase A2 activity, and coronary artery disease (Arvind et al, 2014;Grallert et al, 2012;Ma et al, 2010;Postmus et al, 2014;van der Harst and Verweij, 2018). While rs72703203 is not in high LD with previously reported variants ( Figure S2), it is not significant (p=0.21) in a model that includes rs12740374, a 3' UTR variant in SORT1 proposed as the causal variant in this region (Musunuru and Kathiresan, 2019). We identified an association between rs2274911 (p.Pro91Ser, MAF=26.7%) in GPRC6A and prostate cancer (p=8.2x10 -8 , OR=1.12, 95% CI: 1.07-1.17).…”

Section: Associations With Binary Medical Phenotypesmentioning

confidence: 77%

Medical relevance of common protein-altering variants in GPCR genes across 337,205 individuals in the UK Biobank

DeBoever

Venkatakrishnan

Paggi

et al. 2019

Preprint

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G protein-coupled receptors (GPCRs) drive an array of important physiological functions and are the targets of nearly one-third of all FDA approved drugs. Large scale genomic initiatives are mapping the genetic diversity in GPCRs, however, a map of which GPCR genetic variants are associated with phenotypic variation and disease is lacking. Furthermore, the mechanistic basis of how the individual GPCR genetic variants regulate molecular function is also largely unknown. We performed a phenome-wide association analysis for 269 common protein-altering variants in 156 GPCRs and 275 phenotypes using data from 337,205 unrelated white British UK Biobank participants and identified 138 associations at a false discovery rate of 5%. We found a novel association between rs12295710 in MRGPRE, a member of the Mas-related receptor family involved in nociception, and migraine risk. We also identified an association between rs3732378, a missense mutation in the binding pocket of CX3CR1, and hypothyroidism. Five orphan GPCRs had eight genetic associations, highlighting novel biology for these receptors of unknown function. We found several associations between GPCR variants and food intake phenotypes, including an association between the variants in TAS2R38 known to affect the ability to taste phenylthiocarbamide and tea intake as well as a non-additive associations between variants in TAS2R19 and TAS2R31 and coffee and tea intake. Finally, we tested whether genetic variants in ADRB2 associated with immune cell amounts and pulmonary function affect downstream signaling pathways and found that two ADRB2 haplotypes are associated with differential signaling relative to the most common haplotype. Overall, this study provides a map of genetic associations for GPCR coding variants across a wide variety of phenotypes that can inform future drug discovery efforts targeting GPCRs.

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Section: Associations With Binary Medical Phenotypesmentioning

confidence: 77%

Medical relevance of common protein-altering variants in GPCR genes across 337,205 individuals in the UK Biobank

DeBoever

Venkatakrishnan

Paggi

et al. 2019

Preprint

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“…The differences in prevalence were accompanied by differences in AF symptoms, management, response to anticoagulants, and outcomes for these populations [101]. Another example is coronary artery disease genetics, which also varies in prevalence among populations [102]. In addition, breast cancer incidence is higher for Puerto Ricans and Cuban Latinas than for those from Mexico [103], and there are statistical differences by national origin in the rates of prostate, colorectal, lung, and liver cancers [103].…”

Section: Abbreviationsmentioning

confidence: 99%

Future Preventive Gene Therapy of Polygenic Diseases from a Population Genetics Perspective

Oliynyk

2019

Preprint

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With the accumulation of scientific knowledge of the genetic causes of common diseases and continuous advancement of gene-editing technologies, gene therapies to prevent polygenic diseases may soon become possible. This study endeavored to assess population genetics consequences of such therapies. Computer simulations were used to evaluate the heterogeneity in causal alleles for polygenic diseases that could exist among geographically distinct populations. The results show that although heterogeneity would not be easily detectable by epidemiological studies following population admixture, even significant heterogeneity would not impede the outcomes of preventive gene therapies. Preventive gene therapies designed to correct causal alleles to a naturally-occurring neutral state of nucleotides would lower the prevalence of polygenic early-to middle-age-onset diseases in proportion to the decreased population relative risk attributable to the edited alleles. The outcome would manifest differently for late-onset diseases, for which the therapies would result in a delayed disease onset and decreased lifetime risk, however the lifetime risk would increase again with prolonging population life expectancy, which is a likely consequence of such therapies. If gene therapies that prevent heritable diseases were to be applied on a large scale, the decreasing frequency of risk alleles in populations would reduce the disease risk or delay the age of onset, even with a fraction of the population receiving such therapies. With ongoing population admixture, all groups would benefit over generations.

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“…In addition to lifestyle risk factors such as physical inactivity, unbalanced diet, smoking, alcohol, and obesity (Meier et al, 2019), genetic factors also play a pivotal role in CAD susceptibility (Musunuru and Kathiresan, 2019). Family and twin studies have demonstrated a strong genetic component of CAD, with heritability estimated between 40 and 60% (McPherson and Tybjaerg-Hansen, 2016;Khera and Kathiresan, 2017).…”

Section: Introductionmentioning

confidence: 99%

“…Considering the polygenic nature of CAD, more variants are expected to be identified in the near future owing to the rapid increase in sample size (Zhang et al, 2018). However, the success of GWAS has not been fully translated into an ability to find biological mechanisms and therapeutic targets behind these associations (Shu et al, 2018;Musunuru and Kathiresan, 2019).…”

Section: Introductionmentioning

confidence: 99%

The Integrated Landscape of Biological Candidate Causal Genes in Coronary Artery Disease

Zheng

Chen

et al. 2020

Front. Genet.

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Background: Genome-wide association studies (GWASs) have identified more than 150 genetic loci that demonstrate robust association with coronary artery disease (CAD). In contrast to the success of GWAS, the translation from statistical signals to biological mechanism and exploration of causal genes for drug development remain difficult, owing to the complexity of gene regulatory and linkage disequilibrium patterns. We aim to prioritize the plausible causal genes for CAD at a genome-wide level.Methods: We integrated the latest GWAS summary statistics with other omics data from different layers and utilized eight different computational methods to predict CAD potential causal genes. The prioritized candidate genes were further characterized by pathway enrichment analysis, tissue-specific expression analysis, and pathway crosstalk analysis.Results: Our analysis identified 55 high-confidence causal genes for CAD, among which 15 genes (LPL, COL4A2, PLG, CDKN2B, COL4A1, FES, FLT1, FN1, IL6R, LPA, PCSK9, PSRC1, SMAD3, SWAP70, and VAMP8) ranked the highest priority because of consistent evidence from different data-driven approaches. GO analysis showed that these plausible causal genes were enriched in lipid metabolic and extracellular regions. Tissue-specific enrichment analysis revealed that these genes were significantly overexpressed in adipose and liver tissues. Further, KEGG and crosstalk analysis also revealed several key pathways involved in the pathogenesis of CAD. Conclusion:Our study delineated the landscape of CAD potential causal genes and highlighted several biological processes involved in CAD pathogenesis. Further studies and experimental validations of these genes may shed light on mechanistic insights into CAD development and provide potential drug targets for future therapeutics. HIGHLIGHTS-Conducted an integrative analysis to prioritize the CAD potential causal genes by using eight computational methods. -Identified 55 high-confidence causal genes for CAD, among which 15 genes ranked the highest priority. -Plausible causal genes were enriched in lipid metabolic and extracellular region.

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Genetics of Common, Complex Coronary Artery Disease

Cited by 200 publications

References 118 publications

Medical relevance of common protein-altering variants in GPCR genes across 337,205 individuals in the UK Biobank

Medical relevance of common protein-altering variants in GPCR genes across 337,205 individuals in the UK Biobank

Future Preventive Gene Therapy of Polygenic Diseases from a Population Genetics Perspective

The Integrated Landscape of Biological Candidate Causal Genes in Coronary Artery Disease

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