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From Genotype to Phenotype: A Primer on the Functional Follow-up of Genome-Wide Association Studies in Cardiovascular Disease.

ABSTRACT: Genome-wide association studies (GWASs) have implicated many human genomic loci in the development of complex traits. The loci identified by these studies are potentially involved in novel pathways that contribute to disease pathophysiology. However, eventual therapeutic targeting of these pathways relies on bridging the gap between genetic association and function, a task that first requires validation of causal genetic variants, casual genes, and directionality of effect. Executing this task requires basic knowledge of interpreting GWAS results and prioritizing candidates for further study, in addition to understanding the experimental methods available for evaluating candidate variants. Here we review the basic genetic principles of genome-wide association studies, the computational and experimental tools used for identifying causal variants and genes, and salient illustrative examples of how cardiovascular loci have undergone functional investigation.

SUBMITTER: Lin J

PROVIDER: S-EPMC6003539 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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From Genotype to Phenotype: A Primer on the Functional Follow-up of Genome-Wide Association Studies in Cardiovascular Disease.

Lin Jennie J Musunuru Kiran K

Circulation. Genomic and precision medicine 20180130 2

Genome-wide association studies (GWASs) have implicated many human genomic loci in the development of complex traits. The loci identified by these studies are potentially involved in novel pathways that contribute to disease pathophysiology. However, eventual therapeutic targeting of these pathways relies on bridging the gap between genetic association and function, a task that first requires validation of causal genetic variants, casual genes, and directionality of effect. Executing this task r ...[more]

PMID: 29915816

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Project description:We created a deeply extracted and annotated database of genome-wide association studies (GWAS) results. GRASP v1.0 contains >6.2 million SNP-phenotype association from among 1390 GWAS studies. We re-annotated GWAS results with 16 annotation sources including some rarely compared to GWAS results (e.g. RNAediting sites, lincRNAs, PTMs).To create a high-quality resource to facilitate further use and interpretation of human GWAS results in order to address important scientific questions.GWAS have grown exponentially, with increases in sample sizes and markers tested, and continuing bias toward European ancestry samples. GRASP contains >100 000 phenotypes, roughly: eQTLs (71.5%), metabolite QTLs (21.2%), methylation QTLs (4.4%) and diseases, biomarkers and other traits (2.8%). cis-eQTLs, meQTLs, mQTLs and MHC region SNPs are highly enriched among significant results. After removing these categories, GRASP still contains a greater proportion of studies and results than comparable GWAS catalogs. Cardiovascular disease and related risk factors pre-dominate remaining GWAS results, followed by immunological, neurological and cancer traits. Significant results in GWAS display a highly gene-centric tendency. Sex chromosome X (OR = 0.18[0.16-0.20]) and Y (OR = 0.003[0.001-0.01]) genes are depleted for GWAS results. Gene length is correlated with GWAS results at nominal significance (P ? 0.05) levels. We show this gene-length correlation decays at increasingly more stringent P-value thresholds. Potential pleotropic genes and SNPs enriched for multi-phenotype association in GWAS are identified. However, we note possible population stratification at some of these loci. Finally, via re-annotation we identify compelling functional hypotheses at GWAS loci, in some cases unrealized in studies to date.Pooling summary-level GWAS results and re-annotating with bioinformatics predictions and molecular features provides a good platform for new insights.The GRASP database is available at http://apps.nhlbi.nih.gov/grasp.

Dataset Information

From Genotype to Phenotype: A Primer on the Functional Follow-up of Genome-Wide Association Studies in Cardiovascular Disease.

Publications

From Genotype to Phenotype: A Primer on the Functional Follow-up of Genome-Wide Association Studies in Cardiovascular Disease.

Similar Datasets

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