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Related Concept Videos

Genome-wide Association Studies-GWAS01:11

Genome-wide Association Studies-GWAS

Genome-wide association studies or GWAS are used to identify whether common SNPs are associated with certain diseases. Suppose specific SNPs are more frequently observed in individuals with a particular disease than those without the disease. In that case, those SNPs are said to be associated with the disease. Chi-square analysis is performed to check the probability of the allele likely to be associated with the disease.
GWAS does not require the identification of the target gene involved in...
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A single nucleotide polymorphism or SNP is a single nucleotide variation at a specific genomic position in a large population. It is the most prevalent type of sequence variation found in the human genome. Point mutations that occur in more than 1% of the population qualify as SNPs. These are present once every 1000 nucleotides on an average in the human genome. Replacement of a purine with another purine (A/G) or a pyrimidine with another pyrimidine (C/T) is known as a transition. In contrast,...
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Large-Scale Multi-Omics Genome-Wide Association Studies (Mo-GWAS): Guidelines for Sample Preparation and Normalization
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Published on: July 27, 2021

Identifying multiple causative genes at a single GWAS locus.

Michael J Flister1, Shirng-Wern Tsaih, Caitlin C O'Meara

  • 1Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA;

Genome Research
|September 6, 2013
PubMed
Summary
This summary is machine-generated.

Multiple genes at a single genetic locus can influence hypertension risk. This study used a rat model to show five of six genes at the Agtrap-Plod1 locus impact blood pressure and kidney function.

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Area of Science:

  • Genetics
  • Cardiovascular Disease
  • Genomics

Background:

  • Genome-wide association studies (GWAS) identify candidate genes but struggle with causality and distinguishing variants in linkage disequilibrium (LD).
  • Single GWAS loci may harbor multiple causative genes, yet current GWAS often lack the power to test this hypothesis.
  • Understanding polygenic effects within loci is crucial for advancing genetic disease research.

Purpose of the Study:

  • To empirically test multiple genes within a single GWAS locus for their contribution to hypertension.
  • To investigate the roles of six specific genes (Agtrap, Mthfr, Clcn6, Nppa, Nppb, and Plod1) at the Agtrap-Plod1 locus in a rat model of genetic hypertension.
  • To determine if multiple hypertension-modifying genes can cosegregate within a single locus.

Main Methods:

  • Utilized gene targeting in a disease-susceptible rat model to assess the impact of mutations in six genes at the Agtrap-Plod1 locus.
  • Evaluated effects on blood pressure (BP) and renal phenotypes.
  • Reanalyzed the human AGTRAP-PLOD1 locus to assess the plausibility of polygenic effects in human populations.

Main Results:

  • Five out of the six tested genes significantly impacted hypertension, affecting BP and renal phenotypes.
  • Mutations in Nppa, Plod1, and Mthfr exacerbated hypertension susceptibility.
  • Mutations in Agtrap and Clcn6 conferred a protective effect, reducing hypertension risk.

Conclusions:

  • Demonstrates that multiple genes influencing hypertension can indeed cosegregate at a single GWAS locus.
  • Provides empirical evidence for polygenic effects within a single locus, challenging the limitations of traditional GWAS.
  • Highlights the complexity of genetic architecture in hypertension and suggests a need for refined analytical approaches.