A comparison of the genes and genesets identified by GWAS and EWAS of fifteen complex traits.

Identifying genomic regions pertinent to complex traits is a common goal of genome-wide and epigenome-wide association studies (GWAS and EWAS). GWAS identify causal genetic variants, directly or via linkage disequilibrium, and EWAS identify variation in DNA methylation associated with a trait. While GWAS in principle will only detect variants due to causal genes, EWAS can also identify genes via confounding, or reverse causation. We systematically compare GWAS (N > 50,000) and EWAS (N > 4500) results of 15 complex traits. We evaluate if the genes or gene ontology terms flagged by GWAS and EWAS overlap, and find substantial overlap for diastolic blood pressure, (gene overlap P = 5.2 × 10-6; term overlap P = 0.001). We superimpose our empirical findings against simulated models of varying genetic and epigenetic architectures and observe that in most cases GWAS and EWAS are likely capturing distinct genesets. Our results indicate that GWAS and EWAS are capturing different aspects of the biology of complex traits

Coronary Artery Disease, Genetic Risk and the Metabolome in Young Individuals

Background: Genome-wide association studies have identified genetic variants associated with coronary artery disease (CAD) in adults – the leading cause of death worldwide. It often occurs later in life, but variants may impact CAD-relevant phenotypes early and throughout the life-course. Cohorts with longitudinal and genetic data on thousands of individuals are letting us explore the antecedents of this adult disease. Methods: 149 metabolites, with a focus on the lipidome, measured using nuclear magnetic resonance (1H-NMR) spectroscopy, and genotype data were available from 5,905 individuals at ages 7, 15, and 17 years from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Linear regression was used to assess the association between the metabolites and an adult-derived genetic risk score (GRS) of CAD comprising 146 variants. Individual variant-metabolite associations were also examined. Results: The CAD-GRS associated with 118 of 149 metabolites (false discovery rate [FDR] < 0.05), the strongest associations being with low-density lipoprotein (LDL) and atherogenic non-LDL subgroups. Nine of 146 variants in the GRS associated with one or more metabolites (FDR < 0.05). Seven of these are within lipid loci: rs11591147 PCSK9, rs12149545 HERPUD1-CETP, rs17091891 LPL, rs515135 APOB, rs602633 CELSR2-PSRC1, rs651821 APOA5, rs7412 APOE-APOC1. All associated with metabolites in the LDL or atherogenic non-LDL subgroups or both including aggregate cholesterol measures. The other two variants identified were rs112635299 SERPINA1 and rs2519093 ABO. Conclusions: Genetic variants that influence CAD risk in adults are associated with large perturbations in metabolite levels in individuals as young as seven. The variants identified are mostly within lipid-related loci and the metabolites they associated with are primarily linked to lipoproteins. This knowledge could allow for preventative measures, such as increased monitoring of at-risk individuals and perhaps treatment earlier in life, to be taken years before any symptoms of the disease arise

The Phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P 3 ) Binder Rasa3 Regulates Phosphoinositide 3-kinase (PI3K)-dependent Integrin α IIb β 3 Outside-in Signaling

The class I PI3K family of lipid kinases plays an important role in integrin αIIbβ3 function, thereby supporting thrombus growth and consolidation. Here, we identify Ras/Rap1GAP Rasa3 (GAP1IP4BP) as a major phosphatidylinositol 3,4,5-trisphosphate-binding protein in human platelets and a key regulator of integrin αIIbβ3 outside-in signaling. We demonstrate that cytosolic Rasa3 translocates to the plasma membrane in a PI3K-dependent manner upon activation of human platelets. Expression of wild-type Rasa3 in integrin αIIbβ3-expressing CHO cells blocked Rap1 activity and integrin αIIbβ3-mediated spreading on fibrinogen. In contrast, Rap1GAP-deficient (P489V) and Ras/Rap1GAP-deficient (R371Q) Rasa3 had no effect. We furthermore show that two Rasa3 mutants (H794L and G125V), which are expressed in different mouse models of thrombocytopenia, lack both Ras and Rap1GAP activity and do not affect integrin αIIbβ3-mediated spreading of CHO cells on fibrinogen. Platelets from thrombocytopenic mice expressing GAP-deficient Rasa3 (H794L) show increased spreading on fibrinogen, which in contrast to wild-type platelets is insensitive to PI3K inhibitors. Together, these results support an important role for Rasa3 in PI3K-dependent integrin αIIbβ3-mediated outside-in signaling and cell spreading

The EWAS Catalog: a database of epigenome-wide association studies

Epigenome-wide association studies (EWAS) seek to quantify associations between traits/exposures and DNA methylation measured at thousands or millions of CpG sites across the genome. In recent years, the increase in availability of DNA methylation measures in population-based cohorts and case-control studies has resulted in a dramatic expansion of the number of EWAS being performed and pub-lished. To make this rich source of results more accessible, we have manually curated a database of CpG-trait associations (with p&lt;1x10-4) from published EWAS, each assaying over 100,000 CpGs in at least 100 individuals. From 2021-01-29, The EWAS Catalog contained 1,045,303 associations from over 1000 EWAS. This includes 652,530 associations from 264 peer-reviewed publications. In addi-tion, it also contains summary statistics for 392,773 associations from 428 EWAS, performed in data from the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Gene Expression Om-nibus (GEO). The database is accompanied by a web-based tool and R package, giving researchers the opportunity to quickly and easily query EWAS associations and gain insight into the molecular under-pinnings of disease as well as the impact of traits and exposures on the DNA methylome. The EWAS Catalog is available at: http://www.ewascatalog.org

The EWAS Catalog: a database of epigenome-wide association studies

Epigenome-wide association studies (EWAS) seek to quantify associations between traits/exposures and DNA methylation measured at thousands or millions of CpG sites across the genome. In recent years, the increase in availability of DNA methylation measures in population-based cohorts and case-control studies has resulted in a dramatic expansion of the number of EWAS being performed and published. To make this rich source of results more accessible, we have manually curated a database of CpG-trait associations (with p<1x10 (-4)) from published EWAS, each assaying over 100,000 CpGs in at least 100 individuals. From January 7, 2022, The EWAS Catalog contained 1,737,746 associations from 2,686 EWAS. This includes 1,345,398 associations from 342 peer-reviewed publications. In addition, it also contains summary statistics for 392,348 associations from 427 EWAS, performed on data from the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Gene Expression Omnibus (GEO). The database is accompanied by a web-based tool and R package, giving researchers the opportunity to query EWAS associations quickly and easily, and gain insight into the molecular underpinnings of disease as well as the impact of traits and exposures on the DNA methylome. The EWAS Catalog data extraction team continue to update the database monthly and we encourage any EWAS authors to upload their summary statistics to our website. Details of how to upload data can be found here: http://www.ewascatalog.org/upload. The EWAS Catalog is available at http://www.ewascatalog.org