scholarly journals LocusFocus: A web-based colocalization tool for the annotation and functional follow-up of GWAS

2020 ◽  
Author(s):  
Naim Panjwani ◽  
Fan Wang ◽  
Cheng Wang ◽  
Gengming He ◽  
Scott Mastromatteo ◽  
...  
Keyword(s):  
Association Studies ◽  
Functional Characterization ◽  
Source Code ◽  
High Linkage Disequilibrium ◽  
Genome Wide Association Studies ◽  
Web Based ◽  
Genome Wide ◽  
Responsible Mechanism ◽  
Testing Tool

AbstractGenome-wide association studies (GWAS) have primarily identified trait-associated loci in the non-coding genome. Colocalization analyses of SNP-level associations from GWAS with expression quantitative trait loci (eQTL) evidence enable the generation of hypotheses about responsible mechanism, genes and tissues of origin to guide functional characterization. Here, we present a web-based colocalization browsing and testing tool named LocusFocus (https://locusfocus.research.sickkids.ca). LocusFocus formally tests colocalization using our established Simple Sum method to identify the most relevant genes and tissues for a particular GWAS locus in the presence of high linkage disequilibrium and/or allelic heterogeneity. Full documentation and source code for LocusFocus are publicly available.

scholarly journals Genetics and Epigenetics of Atrial Fibrillation

2020 ◽  
Vol 21 (16) ◽  
pp. 5717 ◽  
Author(s):  
Estefanía Lozano-Velasco ◽  
Diego Franco ◽  
Amelia Aranega ◽  
Houria Daimi
Keyword(s):  
Atrial Fibrillation ◽  
Regulatory Networks ◽  
Association Studies ◽  
Functional Characterization ◽  
The Elderly ◽  
Supraventricular Arrhythmia ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Transcriptional Regulatory ◽  
Transcriptional Regulatory Mechanisms

Atrial fibrillation (AF) is known to be the most common supraventricular arrhythmia affecting up to 1% of the general population. Its prevalence exponentially increases with age and could reach up to 8% in the elderly population. The management of AF is a complex issue that is addressed by extensive ongoing basic and clinical research. AF centers around different types of disturbances, including ion channel dysfunction, Ca2+-handling abnormalities, and structural remodeling. Genome-wide association studies (GWAS) have uncovered over 100 genetic loci associated with AF. Most of these loci point to ion channels, distinct cardiac-enriched transcription factors, as well as to other regulatory genes. Recently, the discovery of post-transcriptional regulatory mechanisms, involving non-coding RNAs (especially microRNAs), DNA methylation, and histone modification, has allowed to decipher how a normal heart develops and which modifications are involved in reshaping the processes leading to arrhythmias. This review aims to provide a current state of the field regarding the identification and functional characterization of AF-related epigenetic regulatory networks

scholarly journals Genome-wide association studies of cardiac electrical phenotypes

2020 ◽  
Vol 116 (9) ◽  
pp. 1620-1634
Author(s):  
Charlotte Glinge ◽  
Najim Lahrouchi ◽  
Reza Jabbari ◽  
Jacob Tfelt-Hansen ◽  
Connie R Bezzina
Keyword(s):  
Genetic Basis ◽  
Association Studies ◽  
Individual Variability ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
Challenges And Opportunities ◽  
Electrocardiographic Parameters

Abstract The genetic basis of cardiac electrical phenotypes has in the last 25 years been the subject of intense investigation. While in the first years, such efforts were dominated by the study of familial arrhythmia syndromes, in recent years, large consortia of investigators have successfully pursued genome-wide association studies (GWAS) for the identification of single-nucleotide polymorphisms that govern inter-individual variability in electrocardiographic parameters in the general population. We here provide a review of GWAS conducted on cardiac electrical phenotypes in the last 14 years and discuss the implications of these discoveries for our understanding of the genetic basis of disease susceptibility and variability in disease severity. Furthermore, we review functional follow-up studies that have been conducted on GWAS loci associated with cardiac electrical phenotypes and highlight the challenges and opportunities offered by such studies.

Efficient estimation of disease odds ratios for follow-up genetic association studies

2017 ◽  
Vol 28 (7) ◽  
pp. 1927-1941
Author(s):  
Jiyuan Hu ◽  
Wei Zhang ◽  
Xinmin Li ◽  
Dongdong Pan ◽  
Qizhai Li
Keyword(s):  
Genetic Association ◽  
Association Studies ◽  
Genetic Association Studies ◽  
Efficient Estimation ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Odds Ratios ◽  
Genome Wide ◽  
Follow Up Studies

In the past decade, genome-wide association studies have identified thousands of susceptible variants associated with complex human diseases and traits. Conducting follow-up genetic association studies has become a standard approach to validate the findings of genome-wide association studies. One problem of high interest in genetic association studies is to accurately estimate the strength of the association, which is often quantified by odds ratios in case-control studies. However, estimating the association directly by follow-up studies is inefficient since this approach ignores information from the genome-wide association studies. In this article, an estimator called GFcom, which integrates information from genome-wide association studies and follow-up studies, is proposed. The estimator includes both the point estimate and corresponding confidence interval. GFcom is more efficient than competing estimators regarding MSE and the length of confidence intervals. The superiority of GFcom is particularly evident when the genome-wide association study suffers from severe selection bias. Comprehensive simulation studies and applications to three real follow-up studies demonstrate the performance of the proposed estimator. An R package, “GFcom”, implementing our method is publicly available at https://github.com/JiyuanHu/GFcom .

scholarly journals Gene-centric functional dissection of human genetic variation uncovers regulators of hematopoiesis

2018 ◽  
Author(s):  
Satish K Nandakumar ◽  
Sean K McFarland ◽  
Laura Marlene Mateyka ◽  
Caleb A Lareau ◽  
Jacob C Ulirsch ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Target Genes ◽  
Association Studies ◽  
Human Diseases ◽  
Genome Wide Association Studies ◽  
Loss Of Function ◽  
Genome Wide ◽  
Causal Variants ◽  
Genomic Regions

Genome-wide association studies (GWAS) have identified thousands of variants associated with human diseases and traits. However, the majority of GWAS-implicated variants are in non-coding genomic regions and require in depth follow-up to identify target genes and decipher biological mechanisms. Here, rather than focusing on causal variants, we have undertaken a pooled loss-of-function screen in primary hematopoietic cells to interrogate 389 candidate genes contained in 75 loci associated with red blood cell traits. Using this approach, we identify 77 genes at 38 GWAS loci, with most loci harboring 1-2 candidate genes. Importantly, the hit set was strongly enriched for genes validated through orthogonal genetic approaches. Genes identified by this approach are enriched in relevant biological pathways, allowing regulators of human erythropoiesis and blood disease modifiers to be defined. More generally, this functional screen provides a paradigm for gene-centric follow up of GWAS for a variety of human diseases and traits.

scholarly journals Genome-wide association studies and contribution to cardiovascular physiology

2015 ◽  
Vol 47 (9) ◽  
pp. 365-375 ◽  
Author(s):  
Patricia B. Munroe ◽  
Andrew Tinker
Keyword(s):  
Complex Traits ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Cardiovascular Disorders ◽  
Genetic Associations ◽  
Physiological Processes ◽  
Genome Wide ◽  
Personal Interests

The study of family pedigrees with rare monogenic cardiovascular disorders has revealed new molecular players in physiological processes. Genome-wide association studies of complex traits with a heritable component may afford a similar and potentially intellectually richer opportunity. In this review we focus on the interpretation of genetic associations and the issue of causality in relation to known and potentially new physiology. We mainly discuss cardiometabolic traits as it reflects our personal interests, but the issues pertain broadly in many other disciplines. We also describe some of the resources that are now available that may expedite follow up of genetic association signals into observations on causal mechanisms and pathophysiology.

scholarly journals Genetics of skin color variation in Europeans: genome-wide association studies with functional follow-up

2015 ◽  
Vol 134 (8) ◽  
pp. 823-835 ◽  
Author(s):  
Fan Liu ◽  
Mijke Visser ◽  
David L. Duffy ◽  
Pirro G. Hysi ◽  
Leonie C. Jacobs ◽  
...  
Keyword(s):  
Skin Color ◽  
Association Studies ◽  
Color Variation ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide

scholarly journals Clap de fin pour le « gène de l’homosexualité »

2020 ◽  
Vol 36 (2) ◽  
pp. 181-184
Author(s):  
Bertrand Jordan
Keyword(s):  
Association Studies ◽  
Single Gene ◽  
Genome Wide Association Studies ◽  
Linkage Studies ◽  
Phenotypic Data ◽  
Genome Wide ◽  
Large Databases ◽  
Very Large Databases ◽  
Small Set

Evidence for a “homosexuality gene” was claimed in the early 1990’s on the basis of linkage studies that, by current criteria, were woefully underpowered. Indeed, follow up studies gave contradictory results. Genome-wide association studies, and very large databases with detailed genetic and phenotypic data, have made possible a re-examination of this issue. While modest heritability (ca. 0.3) for homosexuality is confirmed, no major locus is found and the genetic influence appears extremely polygenic. Thus, there is no single gene, or even small set of genes, that have a strong influence on homosexuality.

VEGAS2: Software for More Flexible Gene-Based Testing

2014 ◽  
Vol 18 (1) ◽  
pp. 86-91 ◽  
Author(s):  
Aniket Mishra ◽  
Stuart Macgregor
Keyword(s):  
Association Studies ◽  
Genome Wide Association Studies ◽  
Command Line ◽  
Single Nucleotide ◽  
Web Based ◽  
Reference Set ◽  
Genome Wide ◽  
User Friendly ◽  
Further Development ◽  
Command Line Version

Gene-based tests such as versatile gene-based association study (VEGAS) are commonly used following per-single nucleotide polymorphism (SNP) GWAS (genome-wide association studies) analysis. Two limitations of VEGAS were that the HapMap2 reference set was used to model the correlation between SNPs and only autosomal genes were considered. HapMap2 has now been superseded by the 1,000 Genomes reference set, and whereas early GWASs frequently ignored the X chromosome, it is now commonly included. Here we have developed VEGAS2, an extension that uses 1,000 Genomes data to model SNP correlations across the autosomes and chromosome X. VEGAS2 allows greater flexibility when defining gene boundaries. VEGAS2 offers both a user-friendly, web-based front end and a command line Linux version. The online version of VEGAS2 can be accessed through https://vegas2.qimrberghofer.edu.au/. The command line version can be downloaded from https://vegas2.qimrberghofer.edu.au/zVEGAS2offline.tgz. The command line version is developed in Perl, R and shell scripting languages; source code is available for further development.

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