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Genome-wide Association Studies-GWAS01:11

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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.
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Splicing is the process by which eukaryotic RNA is edited before its translation into protein. The RNA strand transcribed from eukaryotic DNA is called the primary transcript. The primary transcripts that become mRNAs are called precursor messenger RNAs (pre-mRNAs). Eukaryotic pre-mRNA contains alternating sequences of exons and introns. Exons are nucleotide sequences that code for proteins, whereas introns are the non-coding regions. In RNA splicing, introns are removed and exons are bonded...
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Alternative RNA splicing is the regulated splicing of exons and introns to produce different mature mRNAs from a single pre-mRNA. Unlike in constitutive splicing where a single gene produces a single type of mRNA, alternative splicing allows an organism to produce multiple proteins from a single gene and plays an important role in protein diversity.
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Tissue-specific transcription factors contribute to diverse cellular functions in mammals. For example, the gene for beta globin, a major component of hemoglobin, is present in all cells of the body. However, it is only expressed in red blood cells because the transcription factors that can bind to the promoter sequences of the beta globin gene are only expressed in these cells. Tissue-specific transcription factors also ensure that mutations in these factors may impair only the function of...
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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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Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells
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A multi-tissue, splicing-based joint transcriptome-wide association study identifies susceptibility genes for breast

Guimin Gao1, Julian McClellan1, Alvaro N Barbeira2

  • 1Department of Public Health Sciences, University of Chicago, Chicago, IL 60637, USA.

American Journal of Human Genetics
|May 11, 2024
PubMed
Summary

This study introduces a multi-tissue joint splicing transcriptome-wide association study (splicing-TWAS) to identify breast cancer susceptibility genes. The novel approach significantly enhances gene discovery compared to traditional methods, highlighting the importance of splicing quantitative trait loci (sQTLs).

Keywords:
alternative splicingbreast cancerintron excisionjoint analysismulti-tissuesusceptibility genestranscriptome-wide association studies

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Area of Science:

  • Genetics and Genomics
  • Cancer Research
  • Bioinformatics

Background:

  • Splicing-based transcriptome-wide association studies (splicing-TWASs) are valuable for identifying breast cancer susceptibility genes.
  • Existing splicing-TWASs are limited by focusing solely on breast tissue and individual excised introns, reducing their detection power.
  • Genome-wide association studies (GWAS) have identified numerous genetic loci associated with breast cancer risk.

Purpose of the Study:

  • To develop and apply a multi-tissue joint splicing-TWAS to increase the power of identifying breast cancer susceptibility genes.
  • To integrate splicing signals from multiple excised introns across various relevant tissues.
  • To compare the findings with traditional gene-expression-based TWAS and identify novel associations.

Main Methods:

  • Conducted a multi-tissue joint splicing-TWAS integrating signals from 11 potentially relevant tissues.
  • Utilized summary statistics from a large meta-analysis of GWAS data from 424,650 women of European ancestry.
  • Trained splicing-level prediction models using GTEx (v.8) data and compared results with gene-expression TWAS.

Main Results:

  • Identified 240 genes using the multi-tissue joint splicing-TWAS and nine additional genes via tissue-specific analysis.
  • Discovered 88 novel genes in 62 loci not previously reported by TWAS, and 17 genes in seven loci distant from known GWAS variants.
  • Found 110 genes identified exclusively by splicing-TWAS, indicating that splicing quantitative trait loci (sQTLs) have a stronger impact than expression quantitative trait loci (eQTLs) for many genes.

Conclusions:

  • The multi-tissue joint splicing-TWAS significantly enhances the discovery of breast cancer susceptibility genes.
  • Splicing variations, particularly intron excision events, play a crucial role in breast cancer risk for many genes.
  • This approach provides a more comprehensive understanding of genetic contributions to breast cancer beyond traditional gene expression.